WO2020031087A1 - Polythérapie - Google Patents

Polythérapie Download PDF

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WO2020031087A1
WO2020031087A1 PCT/IB2019/056689 IB2019056689W WO2020031087A1 WO 2020031087 A1 WO2020031087 A1 WO 2020031087A1 IB 2019056689 W IB2019056689 W IB 2019056689W WO 2020031087 A1 WO2020031087 A1 WO 2020031087A1
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Prior art keywords
dose
binding protein
agonist
icos
seq
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PCT/IB2019/056689
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English (en)
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Marc BALLAS
Bruce A. HUG
Christopher MATHENY
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Glaxosmithkline Intellectual Property Development Limited
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Publication of WO2020031087A1 publication Critical patent/WO2020031087A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the present invention relates to a method of treating cancer in a mammal and to combinations useful in such treatment.
  • the present invention relates to combinations of TLR4 agonists and anti-ICOS antibodies.
  • cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death and is characterized by the proliferation of malignant cells which have the potential for unlimited growth, local expansion and systemic metastasis.
  • Deregulation of normal processes includes abnormalities in signal transduction pathways and response to factors that differ from those found in normal cells.
  • Immunotherapies are one approach to treat hyperproliferative disorders.
  • a major hurdle that scientists and clinicians have encountered in the development of various types of cancer immunotherapies has been to break tolerance to self antigen (cancer) in order to mount a robust anti-tumor response leading to tumor regression.
  • cancer immunotherapies target cells of the immune system that have the potential to generate a memory pool of effector cells to induce more durable effects and minimize recurrences.
  • ICOS is a co-stimulatory T cell receptor involved in multiple processes of the immune system.
  • Antigen binding proteins and antibodies that bind ICOS receptor and modulate ICOS signaling are known in the art and are disclosed as immunotherapy, for example, for cancer.
  • Aminoalkyl glucosaminide phosphates (AGPs) are synthetic ligands of Toll-like
  • TLR4 Receptor 4
  • a method of treating cancer in a human in need thereof comprising administering to the human a TLR4 agonist at a dose of about 5 ng to about 1000 ng, and administering to the human an agonist ICOS binding protein or antigen binding portion thereof at a dose of about 24 mg to about 240 mg.
  • a method of treating cancer in a human in need thereof comprising administering to the human a TLR4 agonist at a dose of 50 ng, 100 ng, 150 ng, 200 ng, 250 ng, 300 ng, 350 ng, 400 ng, 450 ng, 500 ng, 550 ng, or 600 ng and administering to the human an ICOS binding protein or antigen binding portion thereof at a dose of 80 mg or 24 mg, wherein the ICOS binding protein comprises a VH domain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:7 and/or a VL domain comprising an amino acid sequence at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 8 wherein said ICOS binding protein specifically binds to human ICOS, and wherein the TLR agonist is CRX-601
  • a TLR4 agonist and an agonist ICOS binding protein for simultaneous or sequential use in treating cancer wherein the TLR4 agonist is to be administered at a dose of about 5 ng to about 1000 ng, and the agonist ICOS binding protein or antigen binding portion thereof is to be administered at a dose of about 24 mg to about 240 mg.
  • a TLR4 agonist for use in treating cancer wherein the TLR4 agonist is to be administered at a dose of about 5 ng to about 1000 ng and is to be administered simultaneously or sequentially with an agonist ICOS binding protein or antigen binding portion thereof at a dose of about 24 mg to about 240 mg.
  • an agonist ICOS binding protein or antigen binding portion thereof for use in treating cancer, wherein the agonist ICOS binding protein or antigen binding portion thereof is to be administered at a dose of about 24 mg to about 240 mg and is to be administered simultaneously or sequentially with a TLR4 agonist at a dose of about 5 ng to about 1000 ng.
  • TLR4 agonist in the manufacture of a medicament for treating cancer, wherein the TLR4 agonist is to be administered at a dose of about 5 ng to about 1000 ng and is to be administered simultaneously or sequentially with an agonist ICOS binding protein or antigen binding portion thereof at a dose of about 24 mg to about 240 mg.
  • an agonist ICOS binding protein or antigen binding portion thereof in the manufacture of a medicament for treating cancer is provided, wherein the agonist ICOS binding protein or antigen binding portion thereof is to be administered at a dose of about 24 mg to about 240 mg and is to be administered simultaneously or sequentially with a TLR4 agonist at a dose of about 5 ng to about 1000 ng.
  • a pharmaceutical kit comprising about 5 ng to about 1000 ng of a TLR4 agonist and about 24 mg to about 240 mg of an agonist ICOS binding protein or antigen binding portion thereof.
  • FIG. 1 is a plot showing CT-26 tumor growth in Balb/c Mice Treated with CRX-601 (TLR4 agonist) and/or ICOS agonist antibody (7E.17G9, mouse surrogate for H2L5 IgG4PE)
  • FIG. 2 is a plot showing survival of Balb/c mice implanted with CT-26 tumors and treated with CRX-601 (TLR4 agonist) and/or ICOS agonist antibody (7E.17G9, mouse surrogate for H2L5 IgG4PE).
  • Antigen Binding Protein means a protein that binds an antigen, including antibodies or engineered molecules that function in similar ways to antibodies. Such alternative antibody formats include triabody, tetrabody, miniantibody, and a minibody. Also included are alternative scaffolds in which the one or more CDRs of any molecules in accordance with the disclosure can be arranged onto a suitable non-immunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U.S. Patent Application Publication Nos. 2005/0053973, 2005/0089932, 2005/0164301) or an EGF domain.
  • a suitable non-immunoglobulin protein scaffold or skeleton such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U.S. Patent Application Publication Nos. 2005/0053973, 2005/0089932, 2005
  • An ABP also includes antigen binding fragments of such antibodies or other molecules.
  • an ABP may comprise the VH regions of the invention formatted into a full length antibody, a (Fab’)2 fragment, a Fab fragment, a bi-specific or biparatopic molecule or equivalent thereof (such as scFV, bi- tri or tetra-bodies, Tandabs, etc), when paired with an appropriate light chain.
  • the ABP may comprise an antibody that is an IgGl, IgG2, IgG3, or IgG4; or IgM; IgA, IgE or IgD or a modified variant thereof.
  • the constant domain of the antibody heavy chain may be selected accordingly.
  • the light chain constant domain may be a kappa or lambda constant domain.
  • the ABP may also be a chimeric antibody of the type described in WO86/01533, which comprises an antigen binding region and a non-immunoglobulin region.
  • the terms “ABP,”“antigen binding protein,” and“binding protein” are used interchangeably herein.
  • ICOS means any Inducible T-cell costimulator protein.
  • ICOS Inducible T-cell COStimulator
  • AILIM Inducible T-cell COStimulator
  • CD278 CD278
  • CVID 1 JTT-l or JTT-2
  • MGC39850 MGC39850
  • 8F4 ICOS is a CD28 -superfamily costimulatory molecule that is expressed on activated T cells.
  • the protein encoded by this gene belongs to the CD28 and CTLA-4 cell-surface receptor family. It forms homodimers and plays an important role in cell-cell signaling, immune responses, and regulation of cell
  • amino acid sequence of human ICOS (isoform 1) (Accession No.: UniProtKB - Q9Y6W8-1) is shown below as SEQ ID NO: 10.
  • ICOS-L B7RP-1/B7-H2
  • B7-1 nor B7-2 ligands for CD28 and CTLA4
  • ICOS-L has been shown to bind weakly to both CD28 and CTLA-4 (Yao S et ak,“B7-H2 is a costimulatory ligand for CD28 in human”, Immunity, 34(5); 729-40 (2011)).
  • Expression of ICOS appears to be restricted to T cells. ICOS expression levels vary between different T cell subsets and on T cell activation status.
  • ICOS expression has been shown on resting TH17, T follicular helper (TFH) and regulatory T (Treg) cells; however, unlike CD28; it is not highly expressed on naive THI and TH2 effector T cell populations (Paulos CM et al., “The inducible costimulator (ICOS) is critical for the development of human Thl7 cells”, Sci Transl Med, 2(55); 55ra78 (2010)).
  • ICOS expression is highly induced on CD4+ and CD8+ effector T cells following activation through TCR engagement (Wakamatsu E, et al.,“Convergent and divergent effects of costimulatory molecules in conventional and regulatory CD4+ T cells”, Proc Natl Acad Sci USA, 110(3); 1023-8 (2013)).
  • Co stimulatory signalling through ICOS receptor only occurs in T cells receiving a concurrent TCR activation signal (Sharpe AH and Freeman GJ.“The B7-CD28 Superfamily”, Nat. Rev Immunol, 2(2); 116-26 (2002)).
  • ICOS In activated antigen specific T cells, ICOS regulates the production of both THI and TH2 cytokines including IFN-g, TNF-a, IL-10, IL-4, IL-13 and others. ICOS also stimulates effector T cell proliferation, albeit to a lesser extent than CD28 (Sharpe AH and Freeman GJ.“The B7-CD28 Superfamily”, Nat. Rev Immunol, 2(2); 116-26 (2002)). Antibodies to ICOS and methods of using in the treatment of disease are described, for instance, in WO 2012/131004, US20110243929, and
  • ICOS.33 IgGlf S267E are reproduced below as SEQ ID NOS: 19-20:
  • Exemplary antibodies in WO2018/029474 include STIM003. Sequences of STIM003 are reproduced below as SEQ ID NOS: 21-22.
  • agent directed to ICOS is meant any chemical compound or biological molecule capable of binding to ICOS.
  • the agent directed to ICOS is an ICOS binding protein.
  • the agent directed to ICOS is an ICOS agonist.
  • the term“ICOS binding protein” as used herein refers to antibodies and other protein constructs, such as domains, which are capable of binding to ICOS.
  • the ICOS is human ICOS.
  • the term“ICOS binding protein” can be used interchangeably with“ICOS antigen binding protein.”
  • anti-ICOS antibodies and/or ICOS antigen binding proteins would be considered ICOS binding proteins.
  • “antigen binding protein” is any protein, including but not limited to antibodies, domains and other constructs described herein, that binds to an antigen, such as ICOS.
  • “antigen binding portion” of an ICOS binding protein would include any portion of the ICOS binding protein capable of binding to ICOS, including but not limited to, an antigen binding antibody fragment.
  • the ICOS antibodies of the present invention comprise any one or a combination of the following CDRs:
  • CDRH2 LISIYSDHTNYNQKFQG (SEQ ID NO:2)
  • CDRH3 N Y GNY GWYFDV (SEQ ID NO:3)
  • CDRL1 SASSSVSYMH (SEQ ID NO:4)
  • CDRL2 DTSKLAS (SEQ ID NO:5)
  • CDRL3 FQGSGYPYT (SEQ ID NO:6)
  • the anti-ICOS antibodies of the present invention comprise a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:7.
  • the ICOS binding proteins of the present invention may comprise a heavy chain variable region having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:7.
  • VH Humanized Heavy Chain
  • H2 Humanized Heavy Chain Variable Region
  • the ICOS antibody comprises CDRL1
  • ICOS binding proteins of the present invention comprising the humanized light chain variable region set forth in SEQ ID NO: 8 are designated as“L5.”
  • an ICOS binding protein of the present invention comprising the heavy chain variable region of SEQ ID NO:7 and the light chain variable region of SEQ ID NO:8 can be designated as H2L5 herein.
  • the ICOS binding proteins of the present invention comprise a light chain variable region having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:8.
  • the ICOS binding proteins of the present invention may comprise a light chain variable region having about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:8.
  • VL Humanized Light Chain
  • L5 Humanized Region
  • CDRs or minimum binding units may be modified by at least one amino acid substitution, deletion or addition, wherein the variant antigen binding protein substantially retains the biological characteristics of the unmodified protein, such as an antibody comprising SEQ ID NO:7 and SEQ ID NO:8.
  • CDR H1, H2, H3, Ll, L2, L3 may be modified alone or in combination with any other CDR, in any permutation or combination.
  • a CDR is modified by the substitution, deletion or addition of up to 3 amino acids, for example 1 or 2 amino acids, for example 1 amino acid.
  • the modification is a substitution, particularly a conservative substitution, for example as shown in Table 1 below.
  • the subclass of an antibody determines secondary effector functions, such as complement activation or Fc receptor (FcR) binding and antibody dependent cell cytotoxicity (ADCC) (Huber, et al., Nature 229(5284): 419-20 (1971); Brunhouse, et al., Mol Immunol 16(11): 907-17 (1979)).
  • FcR complement activation or Fc receptor
  • ADCC antibody dependent cell cytotoxicity
  • the effector functions of the antibodies can be taken into account.
  • hlgGl antibodies have a relatively long half life, are very effective at fixing complement, and they bind to both FcyRI and FcyRII.
  • human IgG4 antibodies have a shorter half life, do not fix complement and have a lower affinity for the FcRs.
  • the ICOS antibody is an lgG4 isotype.
  • the ICOS antibody comprises an lgG4 Fc region comprising the replacement S228P and L235E may have the designation IgG4PE.
  • “ICOS-L” and“ICOS Ligand” are used interchangeably and refer to the membrane bound natural ligand of human ICOS.
  • ICOS ligand is a protein that in humans is encoded by the ICOSLG gene.
  • ICOSLG has also been designated as CD275 (cluster of differentiation 275).
  • Pseudonyms for ICOS-L include B7RP-1 and B7-H2.
  • an“immuno-modulator” or“immuno-modulatory agent” refers to any substance including monoclonal antibodies that affects the immune system.
  • the immuno-modulator or immuno-modulatory agent upregulates the immune system.
  • Immuno-modulators can be used as anti-neoplastic agents for the treatment of cancer.
  • immuno-modulators include, but are not limited to, anti -PD- 1 antibodies (Opdivo/nivolumab and Keytruda/pembrolizumab), anti-CTLA-4 antibodies such as ipilimumab (YERVOY), and anti-ICOS antibodies.
  • agonist refers to an antigen binding protein including but not limited to an antibody, which upon contact with a co-signalling receptor causes one or more of the following (1) stimulates or activates the receptor, (2) enhances, increases or promotes, induces or prolongs an activity, function or presence of the receptor and/or (3) enhances, increases, promotes or induces the expression of the receptor.
  • Agonist activity can be measured in vitro by various assays know in the art such as, but not limited to, measurement of cell signalling, cell proliferation, immune cell activation markers, cytokine production. Agonist activity can also be measured in vivo by various assays that measure surrogate end points such as, but not limited to the measurement of T cell proliferation or cytokine production.
  • Antagonist refers to an antigen binding protein including but not limited to an antibody, which upon contact with a co-signalling receptor causes one or more of the following (1) attenuates, blocks or inactivates the receptor and/or blocks activation of a receptor by its natural ligand, (2) reduces, decreases or shortens the activity, function or presence of the receptor and/or (3) reduces, descrease, abrogates the expression of the receptor.
  • Antagonist activity can be measured in vitro by various assays know in the art such as, but not limited to, measurement of an increase or decrease in cell signalling, cell proliferation, immune cell activation markers, cytokine production.
  • Antagonist activity can also be measured in vivo by various assays that measure surrogate end points such as, but not limited to the measurement of T cell proliferation or cytokine production.
  • the term“antibody” is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanized, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., VH, VHH, VL, domain antibody (dAbTM)), antigen binding antibody fragments, Fab, F(ab’) 2 , Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABSTM, etc. and modified versions of any of the foregoing (for a summary of alternative“antibody” formats see, e.g.,
  • Alternative antibody formats include alternative scaffolds in which the one or more
  • CDRs of the antigen binding protein can be arranged onto a suitable non-immunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an FDF receptor class A domain, an avimer (see, e.g., U.S. Patent Application Publication Nos. 2005/0053973, 2005/0089932, 2005/0164301) or an EGF domain.
  • a suitable non-immunoglobulin protein scaffold or skeleton such as an affibody, a SpA scaffold, an FDF receptor class A domain, an avimer (see, e.g., U.S. Patent Application Publication Nos. 2005/0053973, 2005/0089932, 2005/0164301) or an EGF domain.
  • domain refers to a folded protein structure which retains its tertiary structure independent of the rest of the protein. Generally domains are responsible for discrete functional properties of proteins and in many cases may be added, removed or transferred to other proteins without loss of function of
  • single variable domain refers to a folded polypeptide domain comprising sequences characteristic of antibody variable domains. It therefore includes complete antibody variable domains such as VH, VHH and VL and modified antibody variable domains, for example, in which one or more loops have been replaced by sequences which are not characteristic of antibody variable domains, or antibody variable domains which have been truncated or comprise N- or C-terminal extensions, as well as folded fragments of variable domains which retain at least the binding activity and specificity of the full-length domain.
  • a single variable domain is capable of binding an antigen or epitope independently of a different variable region or domain.
  • A“domain antibody” or“dAb (TM) ” may be considered the same as a“single variable domain”.
  • a single variable domain may be a human single variable domain, but also includes single variable domains from other species such as rodent nurse shark and Camelid VHH dAbsTM.
  • Camelid VHH are immunoglobulin single variable domain polypeptides that are derived from species including camel, llama, alpaca, dromedary, and guanaco, which produce heavy chain antibodies naturally devoid of light chains.
  • Such VHH domains may be humanized according to standard techniques available in the art, and such domains are considered to be“single variable domains”.
  • VH includes camelid VHH domains.
  • An antigen binding fragment may be provided by means of arrangement of one or more CDRs on non-antibody protein scaffolds.
  • “Protein Scaffold” as used herein includes but is not limited to an immunoglobulin (Ig) scaffold, for example an IgG scaffold, which may be a four chain or two chain antibody, or which may comprise only the Fc region of an antibody, or which may comprise one or more constant regions from an antibody, which constant regions may be of human or primate origin, or which may be an artificial chimera of human and primate constant regions.
  • Ig immunoglobulin
  • the protein scaffold may be an Ig scaffold, for example an IgG, or IgA scaffold.
  • the IgG scaffold may comprise some or all the domains of an antibody (i.e. CH1, CH2, CH3, VH, VL).
  • the antigen binding protein may comprise an IgG scaffold selected from IgGl, IgG2, IgG3, IgG4 or IgG4PE.
  • the scaffold may be IgGl .
  • the scaffold may consist of, or comprise, the Fc region of an antibody, or is a part thereof.
  • Affinity is the strength of binding of one molecule, e.g. an antigen binding protein of the invention, to another, e.g. its target antigen, at a single binding site.
  • the binding affinity of an antigen binding protein to its target may be determined by equilibrium methods (e.g. enzyme-linked immunoabsorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetics (e.g. BIACORETM analysis).
  • Avidity is the sum total of the strength of binding of two molecules to one another at multiple sites, e.g. taking into account the valency of the interaction.
  • isolated it is intended that the molecule, such as an antigen binding protein or nucleic acid, is removed from the environment in which it may be found in nature.
  • the molecule may be purified away from substances with which it would normally exist in nature.
  • the mass of the molecule in a sample may be 95% of the total mass.
  • expression vector means an isolated nucleic acid which can be used to introduce a nucleic acid of interest into a cell, such as a eukaryotic cell or prokaryotic cell, or a cell free expression system where the nucleic acid sequence of interest is expressed as a peptide chain such as a protein.
  • Such expression vectors may be, for example, cosmids, plasmids, viral sequences, transposons, and linear nucleic acids comprising a nucleic acid of interest.
  • Expression vectors within the scope of the disclosure may provide necessary elements for eukaryotic or prokaryotic expression and include viral promoter driven vectors, such as CMV promoter driven vectors, e.g., pcDNA3.1, pCEP4, and their derivatives, Baculovirus expression vectors, Drosophila expression vectors, and expression vectors that are driven by mammalian gene promoters, such as human Ig gene promoters.
  • viral promoter driven vectors such as CMV promoter driven vectors, e.g., pcDNA3.1, pCEP4, and their derivatives
  • Baculovirus expression vectors e.g., pcDNA3.1, pCEP4, and their derivatives
  • Baculovirus expression vectors e.g., pcDNA3.1, pCEP4, and their derivatives
  • Baculovirus expression vectors e.g., pcDNA3.1, pCEP4 and their derivatives
  • Drosophila expression vectors e.g.,
  • recombinant host cell means a cell that comprises a nucleic acid sequence of interest that was isolated prior to its introduction into the cell.
  • the nucleic acid sequence of interest may be in an expression vector while the cell may be prokaryotic or eukaryotic.
  • exemplary eukaryotic cells are mammalian cells, such as but not limited to, COS-l, COS-7, HEK293, BHK21, CHO, BSC-l, HepG2, 653, SP2/0, NS0, 293, HeLa, myeloma, lymphoma cells or any derivative thereof.
  • the eukaryotic cell is a HEK293, NS0, SP2/0, or CHO cell.
  • E. coli is an exemplary prokaryotic cell.
  • a recombinant cell according to the disclosure may be generated by transfection, cell fusion, immortalization, or other procedures well known in the art.
  • a nucleic acid sequence of interest, such as an expression vector, transfected into a cell may be extrachromasomal or stably integrated into the chromosome of the cell.
  • A“chimeric antibody” refers to a type of engineered antibody which contains a naturally-occurring variable region (light chain and heavy chains) derived from a donor antibody in association with light and heavy chain constant regions derived from an acceptor antibody.
  • A“humanized antibody” refers to a type of engineered antibody having its CDRs derived from a non-human donor immunoglobulin, the remaining immunoglobulin- derived parts of the molecule being derived from one or more human immunoglobulin(s).
  • framework support residues may be altered to preserve binding affinity (see, e.g., Queen et al. Proc. Natl Acad Sci USA, 86: 10029-10032 (1989), Hodgson, et al,
  • a suitable human acceptor antibody may be one selected from a conventional database, e.g., the KABATTM database, Los Alamos database, and Swiss Protein database, by homology to the nucleotide and amino acid sequences of the donor antibody.
  • a human antibody characterized by a homology to the framework regions of the donor antibody (on an amino acid basis) may be suitable to provide a heavy chain constant region and/or a heavy chain variable framework region for insertion of the donor CDRs.
  • a suitable acceptor antibody capable of donating light chain constant or variable framework regions may be selected in a similar manner. It should be noted that the acceptor antibody heavy and light chains are not required to originate from the same acceptor antibody.
  • the prior art describes several ways of producing such humanized antibodies - see, for example, EP-A-0239400 and EP-A-054951.
  • Fully human antibody includes antibodies having variable and constant regions (if present) derived from human germline immunoglobulin sequences.
  • the human sequence antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site- specific mutagenesis in vitro or by somatic mutation in vivo).
  • Fully human antibodies comprise amino acid sequences encoded only by polynucleotides that are ultimately of human origin or amino acid sequences that are identical to such sequences.
  • antibodies encoded by human immunoglobulin-encoding DNA inserted into a mouse genome produced in a transgenic mouse are fully human antibodies since they are encoded by DNA that is ultimately of human origin. In this situation, human
  • immunoglobulin-encoding DNA can be rearranged (to encode an antibody) within the mouse, and somatic mutations may also occur.
  • Antibodies encoded by originally human DNA that has undergone such changes in a mouse are fully human antibodies as meant herein.
  • the use of such transgenic mice makes it possible to select fully human antibodies against a human antigen.
  • fully human antibodies can be made using phage display technology wherein a human DNA library is inserted in phage for generation of antibodies comprising human germline DNA sequence.
  • the term“donor antibody” refers to an antibody that contributes the amino acid sequences of its variable regions, CDRs, or other functional fragments or analogs thereof to a first immunoglobulin partner. The donor, therefore, provides the altered
  • immunoglobulin coding region and resulting expressed altered antibody with the antigenic specificity and neutralising activity characteristic of the donor antibody.
  • acceptor antibody refers to an antibody that is heterologous to the donor antibody, which contributes all (or any portion) of the amino acid sequences encoding its heavy and/or light chain framework regions and/or its heavy and/or light chain constant regions to the first immunoglobulin partner.
  • a human antibody may be the acceptor antibody.
  • VH and VL are used herein to refer to the heavy chain variable region and light chain variable region respectively of an antigen binding protein.
  • CDRs are defined as the complementarity determining region amino acid sequences of an antigen binding protein. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, “CDRs” as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.
  • TUR4“modulators that is, molecules that modulate TUR4, for example, by binding and initiating conformational changes or signaling by engaging TUR4, molecules that block binding with a TUR4 ligand.
  • TUR4 modulators are aminoalkyl glucosaminide phosphate compounds (AGPs).
  • AGPs aminoalkyl glucosaminide phosphate compounds
  • TLR4 recognizes bacterial UPS (lipopolysaccharide) and when activated initiates an innate immune response.
  • AGPs are a monosaccharide mimetic of the lipid A protein of bacterial UPS and have been developed with ether and ester linkages on the“acyl chains” of the compound. Processes for making these compounds are known and disclosed, for example, in WO 2006/016997, U.S. Patent Nos. 7,288,640 and
  • AGP compounds employed in the present invention have the structure set forth in Formula 1 as follows:
  • n 0 to 6
  • n 0 to 4.
  • X is O or S, preferably O;
  • Y is O or NH
  • Z is O or H
  • each Rl, R2, R3 is selected independently from the group consisting of a Cl -20 acyl and a C 1-20 alkyl;
  • R4 is H or Me
  • R5 is selected independently from the group consisting of -H, -OH, -(C1-C4) alkoxy, -P03R8R9, -0P03R8R9, -S03R8, -0S03R8, -NR8R9, -SR8, -CN, -N02, -CHO, -C02R8, and -CONR8R9, wherein R8 and R9 are each independently selected from H and (C1-C4) alkyl; and
  • each R6 and R7 is independently H or P03H2.
  • the configuration of the 3’ stereogenic centers to which the normal fatty acyl residues (that is, the secondary acyloxy or alkoxy residues, e.g., RlO, R20, and R30) are attached is R or S, preferably R (as designated by Cahn-Ingold-Prelog priority rules).
  • Configuration of aglycon stereogenic centers to which R4 and R5 are attached can be R or S. All stereoisomers, both enantiomers and diastereomers, and mixtures thereof, are considered to fall within the scope of the present invention.
  • the number of carbon atoms between heteroatom X and the aglycon nitrogen atom is determined by the variable“n”, which can be an integer from 0 to 4, or an integer from 0 to 2.
  • the chain length of normal fatty acids Rl, R2, and R3 can be from about 6 to about 16 carbons, or from about 9 to about 14 carbons.
  • the chain lengths can be the same or different. Some embodiments include chain lengths where Rl, R2 and R3 are 6 or 10 or 12 or 14.
  • This AGP compound is set forth as the structure in Formula la as follows:
  • Formula la encompasses L/D-seryl, -threonyl, -cysteinyl ether or ester lipid AGPs, both agonists and antagonists.
  • CRX-547 having the structure shown.
  • CRX-547 Still other embodiments include AGPs, such as CRX-602 or CRX-526 providing increased stability to AGPs having shorter secondary acyl or alkyl chains.
  • the TLR4 modulator is an agonist.
  • the TLR4 modulator that is an agonist is selected from the group consisting of: CRX-601, CRX-547, and CRX-527.
  • the composition comprising a TLR4 modulator, such as an AGP is buffered using a zwitterionoic buffer.
  • the zwitterionic buffer is an aminoalkane sulfonic acid or suitable salt. Examples of amninoalkanesulfonic buffers include, but are not limited, to HEPES, HEPPS/EPPS, MOPS, MOBS and PIPES.
  • the buffer is a pharmaceutically acceptable buffer, suitable for use in humans, such as in for use in a commercial injection product.
  • the buffer is HEPES.
  • the combinations of the invention are believed to have utility in disorders wherein the engagement of ICOS and/or TLR4, is beneficial.
  • the present invention thus also provides a combination of the invention, for use in therapy, particularly, in the treatment of disorders wherein the engagement of ICOS and/or TLR4, is beneficial, particularly cancer.
  • a method of treating cancer in a human in need thereof comprising administering to the human a TLR4 agonist at a dose of about 5 ng to about 1000 ng, and administering to the human an agonist ICOS binding protein or antigen binding portion thereof at a dose of about 24 mg to about 240 mg.
  • the human a TLR4 agonist at a dose of about 5 ng to about 1000 ng
  • administering to the human an agonist ICOS binding protein or antigen binding portion thereof at a dose of about 24 mg to about 240 mg.
  • TLR4 agonist is administered at a dose of 50 ng, 100 ng, 150 ng, 200 ng, 250 ng, 300 ng, 350 ng, 400 ng, 450 ng, 500 ng, 550 ng, or 600 ng.
  • the ICOS binding protein or antigen binding portion thereof is administered at a dose of 24 mg, 80 mg, or 240 mg. In one embodiment, the ICOS binding protein or antigen binding portion thereof is administered at a dose of 80 mg.
  • a TLR4 agonist and an agonist ICOS binding protein for simultaneous or sequential use in treating cancer wherein the TLR4 agonist is to be administered at a dose of about 5 ng to about 1000 ng, and the agonist ICOS binding protein or antigen binding portion thereof is to be administered at a dose of about 24 mg to about 240 mg.
  • a TLR4 agonist for use in treating cancer wherein the TLR4 agonist is to be administered at a dose of about 5 ng to about 1000 ng and is to be administered simultaneously or sequentially with an agonist ICOS binding protein or antigen binding portion thereof at a dose of about 24 mg to about 240 mg.
  • an agonist ICOS binding protein or antigen binding portion thereof for use in treating cancer is provided, wherein the agonist ICOS binding protein or antigen binding portion thereof is to be administered at a dose of about 24 mg to about 240 mg and is to be administered simultaneously or sequentially with a TLR4 agonist at a dose of about 5 ng to about 1000 ng.
  • TLR4 agonist in the manufacture of a medicament for treating cancer, wherein the TLR4 agonist is to be administered at a dose of about 5 ng to about 1000 ng and is to be administered simultaneously or sequentially with an agonist ICOS binding protein or antigen binding portion thereof at a dose of about 24 mg to about 240 mg.
  • an agonist ICOS binding protein or antigen binding portion thereof in the manufacture of a medicament for treating cancer is provided, wherein the agonist ICOS binding protein or antigen binding portion thereof is to be administered at a dose of about 24 mg to about 240 mg and is to be administered simultaneously or sequentially with a TLR4 agonist at a dose of about 5 ng to about 1000 ng.
  • a pharmaceutical kit comprising about 5 ng to about 1000 ng of a TLR4 agonist and about 24 mg to about 240 mg of an agonist ICOS binding protein or antigen binding portion thereof.
  • the dose of the TLR4 agonist is in the range of about 5 ng to about 1000 ng. In another embodiment, the dose of the TLR4 agonist is in the range of about 50 ng to about 1000 ng. In one embodiment, the dose of the TLR4 agonist is in the range of about 50 ng to about 800 ng. In one embodiment, dose of the TLR4 agonist is in the range of about 100 ng to about 600 ng. In one embodiment, dose of the TLR4 agonist is in the range of about 150 ng to about 600 ng.
  • the TLR4 agonist is to be administered at a dose of about 5 ng, about 50 ng, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, about 500 ng, about 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, or about 1000 ng.
  • the dose of the ICOS binding protein or antigen binding portion thereof is in the range of about 0.04 mg to about 480 mg. In another embodiment, the dose of the ICOS binding protein or antigen binding portion thereof is in the range of about 0.08 mg to about 240 mg. In another embodiment, the dose of the ICOS binding protein or antigen binding portion thereof is about 0.08 mg, about 0.24 mg, about 0.8 mg, about 2.4 mg, about 8 mg, about 24 mg, about 80 mg, or about 240 mg.
  • the TLR4 agonist is administered via IV injection. In one embodiment, the TLR4 agonist is administered intravenously, intratumorally, or subcutaneously. In another embodiment, the ICOS binding protein or antigen binding portion thereof is administered via IV infusion.
  • the TLR4 agonist is administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days,
  • the ICOS binding protein is administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, or 40 days.
  • the TLR4 agonist is administered once every week, once every two weeks, or once every three weeks.
  • the ICOS binding protein is administered once every week, once every two weeks, or once every three weeks.
  • a TLR4 agonist is administered in a run-in period prior to
  • the TLR4 agonist is administered in a run-in period of between about 1 week to about 3 weeks. In another embodiment, the run-in period is 1 week, 2 weeks, or 3 weeks.
  • the run-in period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, or 40 days.
  • a method of treating cancer in a human in need thereof comprising administering to the human a TLR4 agonist at a dose of 50 ng, 100 ng, 150 ng, 200 ng, 250 ng, 300 ng, 350 ng, 400 ng, 450 ng, 500 ng, 550 ng, or 600 ng and administering to the human an ICOS binding protein or antigen binding portion thereof at a dose of 80 mg or 24 mg, wherein the ICOS binding protein comprises a VH domain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:7 and/or a VL domain comprising an amino acid sequence at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 8 wherein said ICOS binding protein specifically binds to human ICOS, and wherein the TLR agonist is CRX- 601
  • a TLR4 agonist and an agonist ICOS binding protein for simultaneous or sequential use in treating cancer wherein the TLR4 agonist is to be administered at a dose of 50 ng, 100 ng, 150 ng, 200 ng, or 250 ng, and the agonist ICOS binding protein or antigen binding portion thereof is to be administered at a dose of 24 mg or 80 mg, wherein the ICOS binding protein comprises a VH domain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:7 and/or a VL domain comprising an amino acid sequence at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 8 wherein said ICOS binding protein specifically binds to human ICOS, and wherein the TLR agonist is CRX-601
  • TLR4 agonist in the manufacture of a medicament for treating cancer, wherein the TLR4 agonist is to be administered at a dose of dose of 50 ng, 100 ng, 150 ng, 200 ng, or 250 ng and is to be administered simultaneously or sequentially with an agonist ICOS binding protein or antigen binding portion thereof at a dose of 24 mg or 80 mg, wherein the ICOS binding protein comprises a VH domain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO:7 and/or a VL domain comprising an amino acid sequence at least 90% identical to the amino acid sequence as set forth in SEQ ID NO: 8 wherein said ICOS binding protein specifically binds to human ICOS, and wherein the TLR agonist is CRX- 601
  • the human has a solid tumor.
  • the solid tumor is advanced solid tumor.
  • the cancer is selected from head and neck cancer, squamous cell carcinoma of the head and neck (SCCHN), gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma, prostate cancer, colorectal cancer, ovarian cancer and pancreatic cancer.
  • the human has one or more of the following: SCCHN, colorectal cancer (CRC), esophageal, cervical, bladder, breast, head and neck, ovarian, melanoma, renal cell carcinoma (RCC), EC squamous cell, non-small cell lung carcinoma, mesothelioma, and prostate cancer.
  • SCCHN colorectal cancer
  • CRC colorectal cancer
  • RRC renal cell carcinoma
  • EC squamous cell non-small cell lung carcinoma
  • mesothelioma mesothelioma
  • prostate cancer a liquid tumor such as diffuse large B cell lymphoma (DLBCL), multiple myeloma, chronic lyphomblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia and chronic myelogenous leukemia.
  • DLBCL diffuse large B cell lymphoma
  • CLL chronic lyphomblastic leukemia
  • the present disclosure also relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leuk
  • gastrointestinal stromal tumor gastrointestinal stromal tumor
  • testicular cancer gastrointestinal stromal tumor
  • treating means: (1) to ameliorate the condition of one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, (4) to slow the progression of the condition or one or more of the biological manifestations of the condition and/or (5) to cure said condition or one or more of the biological manifestations of the condition by eliminating or reducing to undetectable levels one or more of the biological manifestations of the condition for a period of time considered to be a state of remission for that manifestation without additional treatment over the period of remission.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
  • cancer cancer
  • neoplasm and tumor
  • a cancer cell refers to cells that have undergone a malignant transformation that makes them pathological to the host organism.
  • Primary cancer cells can be readily distinguished from non-cancerous cells by well- established techniques, particularly histological examination.
  • the definition of a cancer cell includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells.
  • a "clinically detectable" tumor is one that is detectable on the basis of tumor mass; e.g., by procedures such as computed tomography (CT) scan, magnetic resonance imaging (MRI), X-ray, ultrasound or palpation on physical examination, and/or which is detectable because of the expression of one or more cancer- specific antigens in a sample obtainable from a patient.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • X-ray X-ray
  • ultrasound or palpation e.g., ultrasound or palpation on physical examination
  • Tumors may be a hematopoietic (or hematologic or hematological or blood-related) cancer, for example, cancers derived from blood cells or immune cells, which may be referred to as“liquid tumors.”
  • hematologic tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom’s macroglobulinemia; lymphomas such as non-Hodgkin’s lymphoma, Hodgkin’s lymphoma; and the like.
  • the cancer may be any cancer in which an abnormal number of blast cells or unwanted cell proliferation is present or that is diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies.
  • Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic or myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promyelocytic or promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or
  • myelomonoblastic leukemia acute monocytic (or monoblastic) leukemia,
  • erythroleukemia and megakaryocytic (or megakaryoblastic) leukemia may be referred together as acute myeloid (or myelocytic or myelogenous) leukemia (AML).
  • Myeloid malignancies also include myeloproliferative disorders (MPD) which include, but are not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or
  • Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which may be referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEBT); as well as myelofibrosis (MFS) with or without agnogenic myeloid metaplasia.
  • myelodysplasia or myelodysplastic syndrome or MDS
  • MDS myelodysplasia
  • RA refractory anemia
  • RAEB refractory anemia with excess blasts
  • RAEBT refractory anemia with excess blasts in transformation
  • MFS myelofibrosis
  • Hematopoietic cancers also include lymphoid malignancies, which may affect the lymph nodes, spleens, bone marrow, peripheral blood, and/or extranodal sites.
  • Lymphoid cancers include B-cell malignancies, which include, but are not limited to, B-cell non- Hodgkin’s lymphomas (B-NHLs).
  • B-NHLs may be indolent (or low-grade), intermediate- grade (or aggressive) or high-grade (very aggressive).
  • Indolent Bcell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL) including nodal MZL, extranodal MZL, splenic MZL and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated- lymphoid tissue (MALT or extranodal marginal zone) lymphoma.
  • FL follicular lymphoma
  • SLL small lymphocytic lymphoma
  • MZL marginal zone lymphoma
  • LPL lymphoplasmacytic lymphoma
  • MALT mucosa-associated- lymphoid tissue
  • Intermediate-grade B- NHLs include mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML).
  • High-grade B-NHLs include Burkitt’s lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL) and lymphoblastic lymphoma.
  • B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV associated (or AIDS related) lymphomas, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma.
  • B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom’s macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphoid (or lymphocytic or lymphoblastic) leukemia, and Castleman’s disease.
  • NHL may also include T-cell non-Hodgkin’s lymphoma s(T-NHLs), which include, but are not limited to T-cell non-Hodgkin’s lymphoma not otherwise specified (NOS), peripheral T- cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T-cell lymphoma, gamma/delta lymphoma, cutaneous T cell lymphoma, mycosis fungoides, and Sezary syndrome.
  • T-NHLs T-cell non-Hodgkin’s lymphoma s(T-NHLs)
  • Hematopoietic cancers also include Hodgkin’s lymphoma (or disease) including classical Hodgkin’s lymphoma, nodular sclerosing Hodgkin’s lymphoma, mixed cellularity Hodgkin’s lymphoma, lymphocyte predominant (LP) Hodgkin’s lymphoma, nodular LP Hodgkin’s lymphoma, and lymphocyte depleted Hodgkin’s lymphoma.
  • Hodgkin’s lymphoma or disease
  • classical Hodgkin’s lymphoma including classical Hodgkin’s lymphoma, nodular sclerosing Hodgkin’s lymphoma, mixed cellularity Hodgkin’s lymphoma, lymphocyte predominant (LP) Hodgkin’s lymphoma, nodular LP Hodgkin’s lymphoma, and lymphocyte depleted Hodgkin’s lymphoma.
  • LP lymphocyte predominant
  • Hematopoietic cancers also include plasma cell diseases or cancers such as multiple myeloma (MM) including smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom’s Macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL).
  • MM multiple myeloma
  • MGUS monoclonal gammopathy of undetermined (or unknown or unclear) significance
  • MGUS monoclonal gammopathy of undetermined (or unknown or unclear) significance
  • plasmacytoma bone, extramedullary
  • LPL lymphoplasmacytic lymphoma
  • Waldenstrom’s Macroglobulinemia plasma cell leukemia
  • AL primary amyloidosis
  • Hematopoietic cancers may also include other cancers of additional hematopoietic cells
  • Tissues which include hematopoietic cells referred herein to as "hematopoietic cell tissues” include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with mucosa (such as the gut-associated lymphoid tissues), tonsils, Peyer's patches and appendix, and lymphoid tissues associated with other mucosa, for example, the bronchial linings.
  • hematopoietic cell tissues include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with mucosa (such as the gut-associated lymphoid tissues), tonsils, Peyer's patches and appendix, and lymphoid tissues associated with other mucosa, for example, the bronchial linings.
  • the methods of the present invention further comprise administering at least one neo-plastic agent to said human.
  • the methods of the present invention may also be employed with other therapeutic methods of cancer treatment.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention.
  • examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita, T.S. Lawrence, and S.A. Rosenberg (editors), l0 th edition (December 5, 2014), Lippincott Williams & Wilkins Publishers.
  • a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule or anti-mitotic agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines,
  • alkylsulfonates such as nitrosoureas, and triazenes
  • antibiotic agents such as actinomycins, anthracyclins, and bleomycins
  • topoisomerase I inhibitors such as camptothecins
  • topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signalling inhibitors; proteasome inhibitors; heat shock protein inhibitors; inhibitors of cancer metabolism; and cancer gene therapy agents such as genetically modified T cells.
  • Examples of a further active ingredient or ingredients for use in combination or co administered with the present methods or combinations are anti -neoplastic agents.
  • anti-neoplastic agents include, but are not limited to, chemotherapeutic agents; immuno-modulatory agents; immuno-modulators; and immunostimulatory adjuvants.
  • CRX-601 and H2L5 IgG4PE combination was evaluated in BALB/c mice implanted with syngeneic CT-26 tumors.
  • Four groups of 10 BALB/c mice with intact immune systems were implanted with CT-26 tumors.
  • the mice received one of the following treatments: placebo, CRX-601 (TLR4 agonist), 7E.17G9 agonist (mouse surrogate ICOS agonist antibody), or the combination of CRX-601 and 7E.17G9 agonist. While the following treatments: placebo, CRX-601 (TLR4 agonist), 7E.17G9 agonist (mouse surrogate ICOS agonist antibody), or the combination of CRX-601 and 7E.17G9 agonist. While the following treatments: placebo, CRX-601 (TLR4 agonist), 7E.17G9 agonist (mouse surrogate ICOS agonist antibody), or the combination of CRX-601 and 7E.17G9 agonist. While the following treatments
  • CRX-601 and 7E.17G9 had very modest effects on tumor growth (FIG. 1), the combination treatment of CRX-601 and 7E.17G9 produced greater activity and durable responses.
  • CRX-601 and 7E.17G9 monotherapies resulted in 10% and 40% of mice that survived more than 100 days respectively, while the combination therapy resulted in 60% tumor free mice that survived more than 100 days (FIG. 2).
  • CRX-601 and H2L5 IgG4PE were also evaluated for cytokine release in PBMCs isolated from 10 donors under resting or pre -stimulation (anti-CD3) conditions.
  • Cytokines IL-2, IL-6, IL-10, IFN-g, and TNF-a
  • CRX-601 10, 100 or 1000 pg/mL
  • H2L5 IgG4PE 0.01, 0.1, 1 or 10 pg/mL
  • Positive cytokine induction by CRX-601 and H2L5 IgG4PE combination was defined as >3-fold increase above that of CRX-601 alone.
  • Part 1 will include a CRX-601 run-in period of 2 weeks (i.e., CRX-601 administration on Days 1 and 8) prior to administration of the combination partner beginning at Day 15. Approximately 5 dose levels of CRX-601 in combination with a single fixed dose level of the combination partner are planned to be evaluated in Part 1. Following protocol amendment, CRX-601 may also be further evaluated by additional routes of
  • expansion cohorts of approximately 6 to 15 participants with squamous cell carcinoma of the head and neck will be enrolled in each combination treatment arm to further evaluate the safety and activity of dose(s) identified in Part 1.
  • the dose(s) of CRX-601 administered in combination with 80 mg H2L5 IGG4PE will be determined based on data from Part 1 and may differ for each combination treatment.
  • additional expansion cohorts in other tumor types may be enrolled, based on emerging nonclinical and clinical data.
  • PK/Pharmacodynamic cohorts for each combination will be opened to enrollment during Part 1 to obtain additional PK and pharmacodynamic data, with an emphasis to obtain insight on the potential impact of the combination treatments on the immune cells and status of the tumor microenvironment, in conjunction with PK and pharmacodynamic markers obtained from blood.
  • Tumor biopsies are required for enrollment to the PK/Pharmacodynamic cohorts, whereas biopsies are strongly encouraged but not mandatory for Part 1 dose escalation cohorts.
  • participants in the PK/Pharmacodynamic cohorts may be enrolled to any dose level which has already been completed and supported by adequate safety and tolerability from dose escalation for that combination. Up to a maximum of 45 participants may be enrolled into the PK/Pharmacodynamic cohorts with up to approximately 6 per dose level for each combination.
  • the number of dose levels which will be needed to identify the target dose level(s) for Part 2 is not known in advance, consequently, the number of participants in the study can only be estimated. It is estimated that up to approximately 162 total participants will be enrolled into the study. Up to approximately 72 participants will be enrolled into Part 1 (dose-escalation) of the study. Additionally, for each combination, up to 6 participants in each dose cohort, and a maximum of approximately 45 participants in total, may be enrolled into the PK/Pharmacodynamic cohort of Part 1. Additional cohorts (up to a maximum of 12 total participants) may be enrolled in Part 1 to allow for evaluation of more dose levels. Up to approximately 45 participants will be enrolled in Part 2
  • Participants will receive the combination of CRX-601 with H2U5 IGG4PE.
  • escalating doses of CRX-601 will be evaluated as guided by the N-CRM approach.
  • participants will receive a single dose level of CRX-601 as identified based on data from Part 1, in combination with H2U5 IGG4PE.
  • the study includes a screening period, a treatment period, and a follow-up period.
  • Participants will be screened for eligibility beginning 4 weeks before the start of treatment.
  • the duration of study treatment is expected to be up to 2 years.
  • the follow-up period will include disease assessments every 12 weeks until documented PD occurs (PFS Follow Up [FU]).
  • PFS progressive disease
  • participants will be contacted every 12 weeks to assess survival status (Survival FU [SFU]) for up to 2 years from the start of the study treatment.
  • This study is designed to evaluate the safety, tolerability, PK, pharmacodynamic, and preliminary clinical activity of CRX-601 administered in combination with other immunotherapies to participants with advanced solid tumors.
  • Part 1 is divided into 3 treatment arms based on the CRX-601 combination partner; Part la, Part lb, or Part lc.
  • Each of the three treatment arms may have up to 5 dose escalation cohorts to investigate the safety and tolerability of escalating doses of CRX-601 with a single dose level of the combination partner.
  • the CRX-601 combination partner is H2L5 IgG4PE 80 mg (Part lb, Part 2b)
  • Part 1 will include a CRX-601 run-in period of 2 weeks (i.e., CRX-601 administration on days 1 and 8) prior to administration of the combinations beginning on day 15 (Week 3). Following protocol amendment, CRX-601 may also be evaluated by additional routes of administration. Safety data will be evaluated according to a Neuenschwander-Continual Reassessment Method (N-CRM) design (Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Statistics Med.
  • N-CRM Neuenschwander-Continual Reassessment Method
  • Part 2 is also divided into 3 treatment arms for the expansion cohorts; Part 2a, Part 2b, or Part 2c.
  • Expansion cohorts of approximately 6 to 15 participants with SCCHN will be enrolled to each combination to further evaluate safety and activity of the dose regimen(s) identified in Part 1.
  • the dose(s) of CRX-601 administered with 80 mg H2L5 IgG4PE will be determined based on data from Part 1 and may differ for each combination treatment.
  • Additional expansion cohorts in other tumor types may be enrolled based on emerging nonclinical and/or clinical data.
  • PK/Pharmacodynamic cohorts will be opened at cleared dose levels for that combination (i.e. the most recent investigated dose level that supported dose escalation) to explore the potential relationships between dose, biological effects in the tumor microenvironment, and tumor response.
  • a particular emphasis in the PK/Pharmacodynamic cohort is placed on evaluating the possible effects of the combination on the immune cells and immune status within the tumor microenvironment.
  • participants must consent to mandatory fresh biopsy collection at baseline and on treatment.
  • An additional radiographic disease assessment will support exploratory investigation of tumor growth kinetics in this cohort. Note that while consent to fresh tumor biopsy is not required for participation in the dose escalation cohorts in Part 1, it is strongly encouraged. Up to 6 participants per dose level may be enrolled into the PK/Pharmacodynamic cohort for each combination.
  • the study includes a screening period, a treatment period, and a follow-up period.
  • Participants will be screened for eligibility beginning 4 weeks before the start of treatment.
  • the duration of study treatment will be up to 2 years.
  • the follow-up period includes disease assessments every 12 weeks until documented PD. Following PD or for participants that discontinue study treatment for PD, participants will be contacted every 12 weeks to assess survival status for 2 years from the start of the study.
  • Additional participants may be enrolled to evaluate additional routes of study treatment administration (e.g., intratumoral administration), additional agents to be used in combination with CRX-601, or additional indications, based on emerging nonclinical and/or clinical data.
  • additional routes of study treatment administration e.g., intratumoral administration
  • additional agents to be used in combination with CRX-601 e.g., CRX-601
  • additional indications based on emerging nonclinical and/or clinical data.
  • Part 1 dose escalation will be performed to identify combination dose levels comprising CRX-601 with 80 mg H2L5 IgG4PE (Part lb).
  • One (1) dose level ofH2L5 IgG4PE with up to 5 dose levels of CRX-601 are planned for evaluation, pending emerging safety and tolerability information as dose escalation proceeds.
  • Part 1 will include a run-in period of 2 weeks in which CRX-601 is administered once- weekly [i.e., administration on day 1 (Week 1) and day 8 (Week 2)] prior to initiation of combination treatment with H2L5 IGG4PE beginning on day 15 (Week 3).
  • the starting schedule for CRX-601 will be at every l-week intervals (Q1W) from Week 1 through Week 12 including the 2-week monotherapy run in period (Week 1 and Week 2). Subsequently, CRX-601 will be administered at every 3-week intervals (Q3W) to coincide with H2L5 IgG4PE dosing. Thus, beginning with Week 12 for Part 1 and Week 13 for Part 2, both CRX-601 and the combination partner will be administered on the same study day at a frequency of Q3W.
  • Cohorts will be opened beginning with 50 ng CRX-601 administered in combination with 80 mg H2L5 IgG4PE. Three (3) or more participants will be enrolled in each cohort. The total number of participants enrolled into each cohort and dose assignments will be guided by safety information from participants receiving the study treatment combinations according to N-CRM modelling (Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Statistics Med. 2008;27:2420- 2439). Sequential cohorts will be enrolled and dose escalation (or de-escalation) will proceed guided by an N-CRM design. Dose escalation for each cohort will proceed independently of the other cohorts, e.g.
  • dose escalation for Part la is not required prior to dose escalation for Part lb or Part lc.
  • the first 3 participants at each dose level will receive study treatment at least 3 days apart (e.g., if the first participant in a cohort were dosed on Monday, the earliest the next participant could be dosed is Thursday).
  • N-CRM analysis will be performed to guide the dose level to which the next 3 participants will be assigned based on DLT frequency.
  • the number of participants allocated to any cohort is an estimate; participants may also be allocated to PK/Pharmacodynamic cohorts at a previous dose level that supported dose escalation.
  • Dose levels -1 are available for H2L5 IgG4PE (24 mg + 50 ng CRX-601) if the target toxicity level is exceeded in Cohort 1 and a dose reduction is needed below planned doses.
  • the N-CRM model-based design is a Bayesian adaptive dose escalation scheme that assumes a 2-parameter logistic model for the toxicity rate as a function of dose. It is a modified version of the original Continual Reassessment Method proposed by O’Quigley J, Pepe M, Fisher L. Continual Reassessment Method: A Practical Design for Phase I Clinical Trials in Cancer. Biometrics. 1990;46:33-48.
  • the N-CRM method is fully adaptive and makes use of all DLT information, therefore is expected to locate the target dose level efficiently. In this case, the model will be applied to the dose escalation decision for CRX-601, which will be performed independently for each combination.
  • Dose escalation decisions will be held after participants within any given cohort have been observed for at least 6 weeks after starting the study treatment.
  • the Fixed and Adaptive Clinical Trial Simulator FACTS [Tessella, Abington, United Kingdom]
  • the N-CRM estimates for each potential dose will provide the posterior probabilities that the DFT rate lies in each of four toxicity ranges:
  • the recommended dose for dose escalation will be the dose with the highest posterior probability of lying in the target toxicity interval with the additional requirement that the sum of the posterior probabilities of the DFT rate lying in the excessive toxicity or unacceptable toxicity range is less than 25%.
  • An updated estimate of the toxicity curve will be provided at the time of each dose escalation meeting. Note that de-escalation as well as escalation is possible using this method. Dose escalation will continue until conditions for either scenario (i) or (ii) are met: i) Six participants have been treated at the current target dose AND
  • the posterior probabilities of the DLT rate lying within the excessive toxicity interval or within the unacceptable toxicity interval sum to less than 25%
  • the posterior probabilities of the DLT rate lying within the excessive toxicity interval or within the unacceptable toxicity interval sum to greater than 25%.
  • No doses are usable (i.e., for all doses, the posterior probabilities of the DLT rate lying within the excessive toxicity interval or within the unacceptable toxicity interval sum to more than 25%)
  • a two-parameter logistic model will be used for N-CRM analysis for dose level selection during the dose escalation phase. This model will estimate the probability of observing a DLT at each dose level in the study as DLT information becomes available.
  • the logistic model that used for describing the dose-toxicity relationship is:
  • pd is the probability of DLT at dose d
  • dm is a reference dose
  • a and b are Bayesian priors.
  • PK/Pharmacodynamic Cohort(s) Characterizing the effects of treatment on the tumor microenvironment is essential to the understanding the mechanism of action of CRX-601 and its combination partners at the site of action. Thus, for each combination of CRX-601 in Part 1, PK/Pharmacodynamic cohorts will be opened to characterize the biological effects in the tumor
  • PK/Pharmacodynamic cohorts with up to 6 participants per dose level, will be opened for CRX-601 dose levels previously cleared for dose escalation.
  • PK, pharmacodynamic markers, and safety samples will be drawn according to Section Error! Reference source not found, to obtain additional PK and pharmacodynamic data.
  • Participants in the PK/Pharmacodynamic cohort may have the dose escalated to a higher completed dose level (not exceeding the target toxicity level) after Week 9 once the necessary PK/Pharmacodynamic procedures and tissue biopsies have been completed.
  • An AE is considered to be a DLT if it is considered by the investigator to be clinically relevant and attributed (definitely, probably, or possibly) to the study treatment and meets at least 1 of the criteria listed in Table . If an AE is considered related to the underlying disease, it is not a DLT.
  • missed study treatments must be limited during the first 6 weeks of dosing. Participants may not miss any study treatment administered Q3W and may not miss more than 1 study treatment administered Q1W.
  • Participants who withdraw from the study before completing 6 weeks of treatment for reasons other than DLT may be replaced. If a participant experiences a DLT during this period, the participant will be discontinued from the study.
  • Part 2 of the study will further characterize the safety and tolerability of CRX-601 administered in combination with H2L5 IgG4PE (Part 2b) in participants with recurrent, locally advanced, or metastatic SCCHN as determined by safety and tolerability results from the respective cohorts in Part 1.
  • Part 2 will also characterize antitumor activity, PK, and pharmacodynamics effects, including effects measured from tumor biopsy.
  • Part 2 may be opened for a given combination before Part 1 has been completed provided a tolerable dose level within or below the target toxicity range has been identified for that combination.
  • the dose of CRX-601 to be administered in the expansion cohort will be based on all available data and may have a DLT frequency within or below the target toxicity range
  • Interim analysis for futility will be performed on an on-going basis for Part 2b, and cohort(s) may be stopped if interim analysis reveals futility. Actual decisions will depend on the totality of the data.
  • the active study investigators, GSK medical monitor, GSK pharmacovigilance physician, GSK statistician, GSK physician(s) independent of the study team and contract organization physicians will be responsible for decisions to escalate doses and to progress from Part 1 of the study to Part 2. Decisions will be based on safety information and other available data from ongoing and prior cohorts. The dose-determination decision and rationale for each cohort will be discussed with investigators during teleconference(s) and documented in writing, with copies maintained at each study site and in the study master file.
  • N-CRM will be used to recommend the next dosing level
  • clinical judgment by the study investigators and GSK study team can override this recommendation or halt enrollment into any cohorts as deemed appropriate at any time during the trial.
  • participant dose escalation will be considered on a case-by-case basis provided the participant has completed at least 6 weeks of study treatment without the occurrence of a
  • the number of dose levels which will be needed to identify the target dose level(s) for Part 2 is not known in advance, consequently, the number of participants in the study can only be estimated. It is estimated that up to approximately 162 total participants will be enrolled into the study. Up to approximately 72 participants will be enrolled into Part 1 (dose-escalation) of the study with approximately 24 participants in each combination. Up to approximately 45 participants will be enrolled in Part 2 (expansion cohorts) of the study with up to 15 participants in Part 2a and 2b and 15 participants in Part 2c. Additionally, for each combination, up to 6 participants in each dose cohort and a maximum of approximately 45 participants in total may be enrolled into the
  • PK/Pharmacodynamic cohorts of Part 1 Additional cohorts (up to a maximum of 12 total participants) may be enrolled in Part 1 to allow for evaluation of additional dose levels of CRX-601.
  • Part 1 if a participant prematurely discontinues before the completion of 6-weeks treatment for reasons other than DUT, a replacement participant may be enrolled at the discretion of the Sponsor in consultation with the investigator. Participants who are dosed with study treatment will not be replaced in Part 2 (expansion cohort) of the study.
  • TDV treatment discontinuation visit
  • Part 2 a participant will be considered to have completed the study if they meet the study completion criteria for Part 1 and:
  • CRF report form
  • eCRF electronic CRF
  • Eligibility criteria require that participants have progressed after standard therapies or are otherwise unsuitable for standard therapies, and the criteria are intended to minimize the risk of adverse reactions to treatment with immunotherapies.
  • a 2-week run-in period for CRX-601 precedes the administration of the combination therapy.
  • the run-in provides an evaluation of monotherapy CRX-601 safety and tolerability in participants with cancer and prevents the administration of combination therapy to participants that experience, with CRX-601 alone, a DLT, unacceptable tolerability, or an increase in ALT to 1.5x ULN and 1.5x baseline.
  • SCCHN was chosen for further study based on observations of responses to other immunotherapies and recognition of the considerable unmet need for this indication. Additionally, since TLR agonists are being developed by different routes of administration, including intratumoral injection, SCCHN is a possible indication for future exploration of alternative approaches to dosing.
  • CRX-601 and H2L5 IgG4PE have been previously administered as monotherapies in studies.
  • the selection of starting combination doses has taken into consideration all available data, including the safety, tolerability, and pharmacology data of monotherapy CRX-601 and monotherapy H2L5 IgG4PE observed in the respective FTIH studies, together with pharmacology and safety data from animal models and human ex vivo (peripheral blood mononuclear cell [PBMC]) assays, conducted under monotherapy and combination conditions.
  • PBMC peripheral blood mononuclear cell
  • the starting dose of CRX-601 is 50 ng administered once-weekly IV. Previously CRX- 601 was administered at doses up to 100 ng IV to healthy participants in the FTIH Study. Based on data from the FTIH study, the starting dose in the current study (50 ng) is expected to produce low level pharmacological effects consistent with TLR4 agonism based on data from the FTIH study. Because robust TLR receptor saturation assays are not available, target engagement by CRX-601 in the FTIH study (204685) was monitored using representative inflammatory cytokine biomarkers.
  • cytokines post-dose elevations of cytokines following administration of CRX-601 in the FTIH study were of a low magnitude compared to historical clinical studies of TLR agonists administered to cancer patients.
  • the peak levels of inflammatory cytokines at 2h such as TNFa (median: 12 pg/ml; min: 6 pg/ml; max: 23 pg/ml) and IL-6 (median: 132 pg/ml; min: 81 pg/ml; max: 184 pg/ml pg/ml, respectively), associated with administration of 100 ng CRX-601 are below levels reported in previous studies of TLR agonists in cancer patients (>1000 pg/ml) (Chow L, Morishima C, Eaton K, Baik C, Goulart BH, Anderson L, et al.
  • CRX-601 dose levels 7 ng, 21 ng, 60 ng, and 100 ng, mean maximum change with 95% Cl in heart rate was 8 + 9, 10 + 18, 18 + 15, 21 ⁇ 5 beats per minute, respectively.
  • a 50 ng starting dose is expected to be associated with modest changes in body temperature and heart rate.
  • H2L5 IgG4PE The starting dose of H2L5 IgG4PE is 80 mg ( ⁇ l mg/kg) IV administered Q3W.
  • doses up to 3mg/kg (-240 mg) Q3W were evaluated as monotherapy.
  • H2L5 IgG4PE can be dosed up to 3 mg/kg (-240 mg).
  • One DLT was reported in one out of 10 participants treated at this dose.
  • the planned dose of H2L5 IgG4PE for evaluation in the present study is 80 mg, or approximately 1/3 the top dose studied to date.
  • H2L5 IgG4PE systemic concentrations at different dose levels have been simulated with a population pharmacokinetic model developed with available clinical data.
  • ICOS receptor occupancy (RO) in the central circulation has been estimated based on predicted H2L5 IgG4PE systemic exposures and potency values for the functional effects of H2L5 IgG4PE characterized from in vitro binding/activation assays. Potency values generated from three different binding/activation assays (Kd, T-cell binding, IFN-g release) were in the range of 0.09 to 4.14 pg/mL.
  • Kd binding/activation assays
  • the corresponding ICOS RO levels with predicted H2L5 IgG4PE systemic exposures at different dose levels are listed in Table .
  • the predicted RO demonstrates that the 80 mg dose (-1 mg/kg) provides adequate level of target engagement across all three approaches.
  • the currently planned 80mg H2L5 IgG4PE dose may be adjusted lower to 24mg based on emerging safety, exposure and/or pharmacodynamic data if agreed by the study investigators and GSK study team.
  • CRX-601 is not expected to significantly alter the safety and tolerability profile of H2L5 IgG4PE.
  • H2L5 IgG4PE did not enhance cytokine induction by CRX-601 in vitro. Based on the nonclinical data, H2L5 IgG4PE is not expected to significantly alter the safety and tolerability profile of CRX-601.
  • the anti-ICOS 7E.17G9 clone was evaluated in the CT26 murine syngeneic tumor model in combination with the TLR4 agonist, CRX-601 in two separate in vivo studies.
  • Female B ALB/c mice bearing CT26 mouse colon carcinoma tumors (n l 0/group), were given twice weekly IP doses of 7E.17G9 at 10 or 100 pg/mouse for 3 weeks alone and in combination with CRX-601 at 5, 10 or 25 pg/mouse. The treatments were well tolerated as no significant loss of body weight was observed in both studies.
  • the tolerability of CRX-601 approximates that of LPS. Therefore, the top dose of CRX-601 for study participants with cancer is expected to be similar to doses of LPS studied in similar populations, namely 2 to 4 ng/kg (i.e., 160 to 320 ng). The top dose of CRX-601 will not exceed approximately 250 ng, which would represent a less than 3-fold escalation beyond the 100 ng dose which has been studied in the FTIH healthy volunteer study.
  • Archival tumor tissue obtained at any time from the initial diagnosis to study entry is preferred, archival tumor specimen is acceptable if it is not feasible to obtain a fresh biopsy.
  • Participants enrolled in a PK/Pharmacodynamic Cohort must provide a fresh biopsy of a tumour lesion not previously irradiated during the screening period and must agree to provide at least one additional on-treatment biopsy.
  • Measurable disease i.e., presenting with at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
  • ANC Absolute neutrophil count
  • ALT alanine aminotransferase
  • CrCl creatinine clearance
  • INR International Normalized Ratio
  • TSH thyroid- stimulating hormone
  • ULN upper limit of normal
  • WNL within normal limits
  • PT prothrombin time
  • PTT partial thromboplastin time
  • Participants must maintain hemoglobin and/or platelet values for at least 2 weeks without transfusion or growth factor support.
  • TSH is not within normal limits at baseline, the participant may still be eligible if total T3 or free T3 and free T4 are within the normal limits
  • Multigated acquisition scan (MUGA) is acceptable if echocardiography is not available Sex
  • a female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
  • SCCHN oral cavity, oropharynx, hypopharynx, or larynx
  • CNS central nervous system
  • Replacement therapy e.g., thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.
  • thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc. is permitted.
  • HBsAg Hepatitis B surface antigen
  • the QTcF is the QT interval corrected for heart rate according to Fridericia’s formula, machine-read or manually over-read.
  • CV cardiovascular
  • Cardiomyopathy myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting within the past 6 months before enrollment.
  • Congestive heart failure (Class II, III, or IV) as defined by the New York Heart Association functional classification system (NYHA: The Criteria Committee of the New York Heart Association (NYHA). Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th Ed. Boston, Mass: Fittle, Brown & Co. 1994:253-256). • Recent (within the past 6 months) history of symptomatic pericarditis.
  • Tumor necrosis factor receptor (TNFR) agonists including 0X40, CD27, CD137 (4-1BB), CD357 (glucocorticoid-induced TNFR family-related gene) at any time.
  • Prior radiation therapy permissible if at least 1 non-irradiated measurable lesion is available for assessment according to RECIST version 1.1 or if a solitary measurable lesion was irradiated, objective progression is documented. A wash out of at least 14 days before start of study treatment for radiation of any intended use to the extremities for bone metastases and 28 days for radiation to the chest, brain, or visceral organs is required. 19. Prior allogeneic or autologous bone marrow transplantation or another solid organ transplantation.
  • Toxicity from previous treatment including:
  • Participants may experience orthostatic dizziness following administration of CRX-601. Precautions should be taken to avoid falls after rising from a lying or seated position for several hours after administration of study treatment. In addition, participants will abstain from strenuous exercise for 8 hours before each blood collection for clinical laboratory tests. Participants may participate in light recreational activities during studies (e.g., watching television, reading).
  • Screen failures are defined as participants who consent to participate in the clinical study but are not subsequently entered in the study.
  • a minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials publishing requirements and to respond to queries from regulatory authorities.
  • Minimal information includes demography, screen failure details, eligibility criteria, and any SAEs. Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened once. This includes retesting specific vital sign measurements, laboratory assessments, etc. that may not have met eligibility criteria.
  • Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol.
  • the term‘study treatment’ is used throughout the protocol to describe any combination of products received by the participant as per the protocol design.
  • TLR agonists have rarely been associated with severe bradycardia or asystole in clinical trials, attributed to poor hydration and/or history of syncope) (van Eijk LT, Pickkers P, Smits P, Bouw MP, van der Hoeven JG. Severe vagal response after endotoxin administration in humans. Intensive Care Med. 2004 Dec;30(l2):2279-8 l . Epub 2004 Oct 26). Oral hydration should be encouraged in the days prior to study treatment and/or IV fluids (e.g., 1 L or as clinically indicated) administered before CRX-601.
  • IV fluids e.g., 1 L or as clinically indicated
  • H2L5 IgG4PE CRX-601 and mAh combination partner H2L5 IgG4PE will be administered to participants at each study site under medical supervision of an investigator or designee. H2L5 IgG4PE will be administered first, and CRX-601 will be administered at least 1 hour after the completion of the mAh infusion. The date and time of administration will be recorded in the source documents and reported in the eCRF.
  • Infusions may be prolonged in the event of an infusion reaction. If multiple participants experience clinically significant infusion reactions, the infusion rate may be slowed for all future administrations of study treatment(s) for all participants. Should this global change in infusion rate be required, it will be communicated to the sites in writing.
  • cytokine-related AEs and infusion reactions include“cytokine-related AEs and infusion reactions” and “immune-related AEs”. Even though both cytokine production and immune activity play roles in both categories of events, the nomenclature is intended to describe distinct classes of AEs, as described below.
  • the dose level of CRX-601 may be changed as determined by the investigator and sponsor. Participants may not discontinue only 1 study treatment. If either study treatment is deemed intolerable and requires discontinuation despite optimal management, as described below, the participant must be discontinued from both study treatments. CRX-601 may be restarted at the next lower dose level, and/or the mAh (H2L5 IgG4PE) at the next lower dose level.
  • Procedures conducted as part of the participant’s routine clinical management (e.g., blood count) and obtained before signing of ICF may be utilized for screening or baseline purposes provided the procedure met the protocol-specified criteria and was performed within the time frame as defined in the Schedule of Activities.
  • assessments are scheduled for the same nominal time, it is recommended that the assessments should occur in the following order: 12-lead ECG, vital signs, and blood draws. The timing of the assessments should allow the blood draw to occur at the exact nominal time.
  • Timing and number of planned study assessments may be altered during the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring for the following assessments: safety, PK, pharmacodynamics/biomarker, or other assessments (not applicable for participants in Canada).
  • the IRB/ IEC will be informed of any safety issues that require alteration of the safety monitoring scheme or amendment of the informed consent form.
  • Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Schedule of Activities, are essential and required for study conduct.
  • Disease assessment modalities may include imaging (e.g., computed tomography [CT] scan, magnetic resonance imaging [MRI], bone scan, plain radiography) and physical examination (as indicated for palpable/superficial lesions). Scans will be collected centrally during the study and may be reviewed or analyzed by an independent central reviewer. Details will be provided in the SRM.
  • imaging e.g., computed tomography [CT] scan, magnetic resonance imaging [MRI], bone scan, plain radiography
  • RECIST version 1.1 guidelines will be used to determine the overall tumor burden at baseline, select target and non-target lesions, and in the disease assessments throughout the duration of the study (Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1). Eur J Cancer. 2009;45:228-247). irRECIST assessments will be evaluated as well. Treatment decisions according to irRECIST are encouraged, including confirmatory disease assessments at least 4 weeks after the date disease progression was declared. Similarly, new lesions should be measured, as feasible, and may be incorporated into assessments of tumor burden according to irRECIST guidelines.
  • Lymph nodes that have a short axis of ⁇ 10 mm are considered non-pathological and should not be recorded or followed.
  • Pathological lymph nodes with >15 mm short axis are considered measurable and can be selected as target lesions, however lymph nodes should not be selected as target lesions when other suitable target lesions are available.
  • Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions, and recorded and measured at baseline. These lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically).
  • Cystic lesions thought to represent cystic metastases should not be selected as target lesions when other suitable target lesions are available.
  • Bone scans fluorodeoxyglucose (FDG)-positron-emission tomography (PET) scans or X-rays are not considered adequate imaging techniques to measure bone lesions.
  • FDG fluorodeoxyglucose
  • PET positron-emission tomography
  • All other lesions should be identified as non-target and should also be recorded at baseline. Non-target lesions will be grouped by organ.
  • CT scan with contrast of the chest, abdomen, and pelvis is required.
  • SCCHN For participants with SCCHN, a scan of the head and neck area is required. Other areas should be evaluated as indicated by the participant’s underlying disease prior to screening, including clinical disease assessment for palpable/visible lesions.
  • CT scan is preferred, MRI may be used as an alternative method of baseline disease assessment, especially for those participants where a CT scan is contraindicated due to allergy to contrast, provided that the method used to document baseline status is used consistently throughout study treatment to facilitate direct comparison. At each post baseline assessment, evaluations of the sites of disease identified by these scans are required.
  • Example 8 Guidelines for Assessment of Disease, Disease Progression and Response Criteria - adapted from RECIST version 1.1
  • Contrast agents must be used in accordance with the Image Acquisition Guidelines.
  • Ultrasound is not a suitable modality of disease assessment. If new lesions are
  • Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing assessments of disease. However, FDG-PET can be useful in confirming new sites of disease where a positive FDG-PET scans correlates with the new site of disease present on CT/MRI or when a baseline FDG-PET was previously negative for the site of the new lesion.
  • FDG-PET may also be used in lieu of a standard bone scan providing coverage allows interrogation of all likely sites of bone disease and FDG-PET is performed at all assessments.
  • CT component can only be used for standard
  • response assessments if performed to diagnostic quality, which includes the required anatomical coverage and prescribed use of contrast.
  • the method of assessment should be noted as CT on the CRF.
  • Clinical Examination Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler/calipers to measure the size of the lesion, is required (Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.
  • Minimum size of a measurable baseline lesion should be twice the slice thickness, with a minimum lesion size of 10 mm when the slice thickness is 5 mm.
  • MRI is acceptable, but when used, the technical specification of the scanning sequences should be optimized for the evaluation of the type and site of disease and lesions must be measured in the same anatomic plane by use of the same imaging examinations. Whenever possible the same scanner should be used (Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1). Eur J Cancer. 2009;45:228-247).
  • X-ray In general, X-ray should not be used for target lesion measurements owing to poor lesion definition. Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung; however, chest CT is preferred over chest X-ray (Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1). Eur J Cancer. 2009;45:228-247).
  • the minimum size of a measurable lesion must be at least double the slice thickness (e.g., if the slice thickness is 10 mm, a measurable lesion must be >20 mm).
  • lymph nodes can be considered pathologically enlarged and measurable if • >l5mm in the short axis when assessed by CT or MRI (slice thickness recommended to be no more than 5mm). At baseline and follow-up, only the short axis will be measured (Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1). Eur J Cancer. 2009;45:228-247).
  • All other lesions including lesions too small to be considered measurable (longest diameter ⁇ 10 mm or pathological lymph nodes with > 10 mm and ⁇ 15 mm short axis) as well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement of the skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques (Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1). Eur J Cancer. 2009;45:228-247).
  • Measurable disease The presence of at least 1 measurable lesion. Palpable lesions that are not measurable by radiologic or photographic evaluations may not be utilized as the only measurable lesion.
  • Non-Measurable only disease The presence of only non-measurable lesions. Note: non- measurable only disease is not allowed per protocol.
  • Treatment decisions may be based upon the immune-related RECIST guidelines.
  • the short axis of the lymph node(s) is added into the sum.
  • the short axis is the longest perpendicular diameter to the longest diameter of a lymph node or nodal mass.
  • Tumor Burden Sum of diameterstarget lesions + sum of diametersnew, measurable lesions Time-point response assessment using the Immune-Related RECIST criteria
  • Percentage changes in tumor burden per assessment time point describe the size and growth kinetics of both conventional and new, measurable lesions as they appear.
  • the response in index and new, measurable lesions is defined based on the change in tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed relative to baseline measurements (i.e., the sum of diameters of all target lesions at screening).
  • ⁇ CR Disappearance of all target lesions. Any pathological lymph nodes must be
  • PR At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change from baseline).
  • PD At least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5mm.
  • lymph nodes are documented as target lesions the short axis is added into the sum of the diameters (e.g., sum of diameters is the sum of the longest diameters for non- nodal lesions and the short axis for nodal lesions).
  • sum of diameters is the sum of the longest diameters for non- nodal lesions and the short axis for nodal lesions.
  • the response assessment should be NE.
  • Non-CR/Non-PD The persistence of 1 or more non-target lesion(s) or lymph nodes identified as a site of disease at baseline > 10 mm short axis.
  • NA No non-target lesions at baseline.
  • NE Not Evaluable
  • New lesions New malignancies denoting disease progression must be unequivocal. Lesions identified in follow-up in an anatomical location not scanned at baseline are considered new lesions.
  • Table presents the overall response at an individual time point for all possible combinations of tumor responses in target and non-target lesions with or without the appearance of new lesions for participants with measurable disease at baseline.
  • Table 8 Evaluation of Overall Response for Participants with Measurable
  • the best overall response is the best response recorded from the start of the treatment until disease progression/recurrence and will be determined programmatically by GSK based on the investigators assessment of response at each time point.
  • a confirmatory disease assessment should be performed no less than 4 weeks (28 days) after the criteria for response are first met.
  • Kidney Disease Outcomes Quality Initiative CKD stages 3/4/5 defined by estimated glomular filtration rate (GFR) using the CKD
  • GFR 141 x min (S cr /K, 1)“ x max(S cr /K, l) 1 209 x 0.993 A s e x 1.018 [if female] x 1.159 [if black]
  • Scr is serum creatinine in mg/dL
  • K is 0.7 for females and 0.9 for males
  • a is -0.329 for females and -0.411 for males

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Abstract

La présente invention concerne un procédé de traitement du cancer chez un être humain en ayant besoin, le procédé comprenant l'administration à cet être humain d'un agoniste de TLR4 à une dose d'environ 5 ng à environ 1000 ng, et l'administration à cet être humain d'une protéine de liaison à ICOS agoniste ou d'une partie de liaison à l'antigène de celle-ci à une dose d'environ 24 mg à environ 240 mg.
PCT/IB2019/056689 2018-08-06 2019-08-06 Polythérapie WO2020031087A1 (fr)

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Citations (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054951A1 (fr) 1980-12-24 1982-06-30 Chugai Seiyaku Kabushiki Kaisha Dibenzo(b,f)(1,4)oxazépines, leur procédé de préparation et les compositions pharmaceutiques les contenant
WO1986001533A1 (fr) 1984-09-03 1986-03-13 Celltech Limited Production d'anticorps chimeriques
EP0239400A2 (fr) 1986-03-27 1987-09-30 Medical Research Council Anticorps recombinants et leurs procédés de production
US6113918A (en) 1997-05-08 2000-09-05 Ribi Immunochem Research, Inc. Aminoalkyl glucosamine phosphate compounds and their use as adjuvants and immunoeffectors
EP1125585A1 (fr) 1999-08-30 2001-08-22 Japan Tobacco Inc. Traitements de maladies immunitaires
WO2001090129A2 (fr) 2000-05-19 2001-11-29 Corixa Corporation Traitement prophylactique et therapeutique de maladies infectieuses et autres avec des composes a base de mono- et disaccharides
US6525028B1 (en) 2002-02-04 2003-02-25 Corixa Corporation Immunoeffector compounds
EP1374902A1 (fr) 2001-03-27 2004-01-02 Japan Tobacco Inc. Remedes contre les affections intestinales inflammatoires
EP1374901A1 (fr) 2001-03-01 2004-01-02 Japan Tobacco, Inc. Dispositifs de rejet du greffon
US20050053973A1 (en) 2001-04-26 2005-03-10 Avidia Research Institute Novel proteins with targeted binding
US20050089932A1 (en) 2001-04-26 2005-04-28 Avidia Research Institute Novel proteins with targeted binding
US6911434B2 (en) 2002-02-04 2005-06-28 Corixa Corporation Prophylactic and therapeutic treatment of infectious and other diseases with immunoeffector compounds
US20050164301A1 (en) 2003-10-24 2005-07-28 Avidia Research Institute LDL receptor class A and EGF domain monomers and multimers
WO2006016997A2 (fr) 2004-07-08 2006-02-16 Corixa Corporation Composes d'aminoalkylglucosaminide phosphate et leur utilisation
US7129219B2 (en) 2000-08-04 2006-10-31 Corixa Corporation Immunoeffector compounds
US7288640B2 (en) 2002-07-08 2007-10-30 Corixa Corporation Processes for the production of aminoalkyl glucosaminide phosphate and disaccharide immunoeffectors, and intermediates therefor
WO2008137915A2 (fr) 2007-05-07 2008-11-13 Medimmune, Llc Anticorps anti-icos et leur utilisation en traitement oncologique, de transplantation et maladie auto-immune
WO2010056804A1 (fr) 2008-11-12 2010-05-20 Medimmune, Llc Formulation d’anticorps
WO2012013004A1 (fr) 2010-07-27 2012-02-02 大连理工大学 Procédé pour le relargage et l'extraction d'acétone et de butanol à partir de liqueur de fermentation
WO2012131004A2 (fr) 2011-03-31 2012-10-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Anticorps dirigés contre icos et utilisation de ceux-ci
WO2014033327A1 (fr) 2012-09-03 2014-03-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Anticorps anti-icos pour le traitement de la réaction greffe contre hôte
US20160215059A1 (en) 2015-01-28 2016-07-28 Glaxosmithkline Intellectual Property Development Limited Icos binding proteins
US20160304610A1 (en) 2015-03-23 2016-10-20 Jounce Therapeutics, Inc. Antibodies to icos
WO2017021792A1 (fr) * 2015-08-06 2017-02-09 Glaxosmithkline Biologicals Sa Agonistes de tlr4, leurs compositions et leur utilisation dans le traitement du cancer
WO2018029474A2 (fr) 2016-08-09 2018-02-15 Kymab Limited Anticorps anti-icos
US20180289790A1 (en) 2017-04-07 2018-10-11 Bristol-Myers Squibb Company Anti-icos agonist antibodies and uses thereof

Patent Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054951A1 (fr) 1980-12-24 1982-06-30 Chugai Seiyaku Kabushiki Kaisha Dibenzo(b,f)(1,4)oxazépines, leur procédé de préparation et les compositions pharmaceutiques les contenant
WO1986001533A1 (fr) 1984-09-03 1986-03-13 Celltech Limited Production d'anticorps chimeriques
EP0239400A2 (fr) 1986-03-27 1987-09-30 Medical Research Council Anticorps recombinants et leurs procédés de production
US6113918A (en) 1997-05-08 2000-09-05 Ribi Immunochem Research, Inc. Aminoalkyl glucosamine phosphate compounds and their use as adjuvants and immunoeffectors
EP1125585A1 (fr) 1999-08-30 2001-08-22 Japan Tobacco Inc. Traitements de maladies immunitaires
WO2001090129A2 (fr) 2000-05-19 2001-11-29 Corixa Corporation Traitement prophylactique et therapeutique de maladies infectieuses et autres avec des composes a base de mono- et disaccharides
US7129219B2 (en) 2000-08-04 2006-10-31 Corixa Corporation Immunoeffector compounds
EP1374901A1 (fr) 2001-03-01 2004-01-02 Japan Tobacco, Inc. Dispositifs de rejet du greffon
EP1374902A1 (fr) 2001-03-27 2004-01-02 Japan Tobacco Inc. Remedes contre les affections intestinales inflammatoires
US20050089932A1 (en) 2001-04-26 2005-04-28 Avidia Research Institute Novel proteins with targeted binding
US20050053973A1 (en) 2001-04-26 2005-03-10 Avidia Research Institute Novel proteins with targeted binding
US6911434B2 (en) 2002-02-04 2005-06-28 Corixa Corporation Prophylactic and therapeutic treatment of infectious and other diseases with immunoeffector compounds
US6525028B1 (en) 2002-02-04 2003-02-25 Corixa Corporation Immunoeffector compounds
US7288640B2 (en) 2002-07-08 2007-10-30 Corixa Corporation Processes for the production of aminoalkyl glucosaminide phosphate and disaccharide immunoeffectors, and intermediates therefor
US20050164301A1 (en) 2003-10-24 2005-07-28 Avidia Research Institute LDL receptor class A and EGF domain monomers and multimers
WO2006016997A2 (fr) 2004-07-08 2006-02-16 Corixa Corporation Composes d'aminoalkylglucosaminide phosphate et leur utilisation
US20110243929A1 (en) 2007-05-07 2011-10-06 Medlmmune, Llc Anti-icos antibodies and their use in treatment of oncology, transplantation and autoimmune disease
WO2008137915A2 (fr) 2007-05-07 2008-11-13 Medimmune, Llc Anticorps anti-icos et leur utilisation en traitement oncologique, de transplantation et maladie auto-immune
WO2010056804A1 (fr) 2008-11-12 2010-05-20 Medimmune, Llc Formulation d’anticorps
WO2012013004A1 (fr) 2010-07-27 2012-02-02 大连理工大学 Procédé pour le relargage et l'extraction d'acétone et de butanol à partir de liqueur de fermentation
WO2012131004A2 (fr) 2011-03-31 2012-10-04 INSERM (Institut National de la Santé et de la Recherche Médicale) Anticorps dirigés contre icos et utilisation de ceux-ci
WO2014033327A1 (fr) 2012-09-03 2014-03-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Anticorps anti-icos pour le traitement de la réaction greffe contre hôte
US20160215059A1 (en) 2015-01-28 2016-07-28 Glaxosmithkline Intellectual Property Development Limited Icos binding proteins
WO2016120789A1 (fr) 2015-01-28 2016-08-04 Glaxosmithkline Intellectual Property Development Limited Protéines de liaison agonistes d' icos
US20160304610A1 (en) 2015-03-23 2016-10-20 Jounce Therapeutics, Inc. Antibodies to icos
WO2017021792A1 (fr) * 2015-08-06 2017-02-09 Glaxosmithkline Biologicals Sa Agonistes de tlr4, leurs compositions et leur utilisation dans le traitement du cancer
WO2018029474A2 (fr) 2016-08-09 2018-02-15 Kymab Limited Anticorps anti-icos
US20180289790A1 (en) 2017-04-07 2018-10-11 Bristol-Myers Squibb Company Anti-icos agonist antibodies and uses thereof

Non-Patent Citations (28)

* Cited by examiner, † Cited by third party
Title
"Cancer Principles and Practice of Oncology", 5 December 2014, LIPPINCOTT WILLIAMS & WILKINS PUBLISHERS
"NYHA: The Criteria Committee of the New York Heart Association (NYHA", vol. 1994, LITTLE, BROWN & CO., article "Nomenclature and criteria for diagnosis of diseases of the heart and great vessels", pages: 253 - 256
"UniProtKB", Database accession no. Q9Y6W8-1
ALEGRE ET AL., J IMMUNOL, vol. 148, no. 11, 1992, pages 3461 - 8
ANGAL ET AL., MOL IMMUNOL, vol. 30, no. 1, 1993, pages 105 - 8
BRUNHOUSE ET AL., MOL IMMUNOL, vol. 16, no. 11, 1979, pages 907 - 17
CHOTHIA ET AL., NATURE, vol. 342, 1989, pages 877 - 883
CHOW LMORISHIMA CEATON KBAIK CGOULART BHANDERSON L ET AL.: "Phase Ib Trial of the Toll-like Receptor 8 Agonist, Motolimod (VTX-2337), Combined with Cetuximab in Patients with Recurrent or Metastatic SCCHN", CLIN CANCER RES., vol. 23, no. 10, 15 May 2017 (2017-05-15), pages 2442 - 2450
DIETSCH GWHITING SNORTHFELT DRAMANATHAN RCOHEN PMANJARREZ K ET AL.: "Comparison of immune modulation by TLR8 agonist vtx-2337 (motolimod) in cancer patients and healthy volunteers", JOURNAL FOR IMMUNOTHERAPY OF CANCER, vol. 2, no. 3, 2014, pages 165
EDELMAN, G.M. ET AL., PROC. NATL. ACAD. USA, vol. 63, 1969, pages 78 - 85
EISENHAUER EATHERASSE PBOGAERTS JSCHWARTZ LHSARGENT DFORD R ET AL.: "New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1", EUR J CANCER, vol. 45, 2009, pages 228 - 247
ENGELHARDT RMACKENSEN AGALANOS C: "Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients", CANCER RES., vol. 51, no. 10, 15 May 1991 (1991-05-15), pages 2524 - 30
HODGSON ET AL., BIO/TECHNOLOGY, vol. 9, 1991, pages 421
HOLLIGERHUDSON, NATURE BIOTECHNOLOGY, vol. 23, no. 9, 2005, pages 1126 - 1136
HUBER ET AL., NATURE, vol. 229, no. 5284, 1971, pages 419 - 20
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
LEVEY ASSTEVENS LASCHMID CHZHANG YCASTRO AFFELDMAN HI ET AL.: "A New Equation to Estimate Glomerular Filtration Rate", ANN INTERN MED., vol. 150, 2009, pages 604 - 612
NEUENSCHWANDER BBRANSON MGSPONER T: "Critical aspects of the Bayesian approach to phase I cancer trials", STATISTICS MED., vol. 27, 2008, pages 2420 - 2439
NISHINO MGIOBBIE-HURDER AGARGANO MSUDA MRAMAIYA NHHODI FS: "Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements", CLIN CANCER RES., vol. 19, 2013, pages 3936 - 3943, XP055157316, DOI: 10.1158/1078-0432.CCR-13-0895
O'QUIGLEY JPEPE MFISHER L: "Continual Reassessment Method: A Practical Design for Phase I Clinical Trials in Cancer", BIOMETRICS, vol. 46, 1990, pages 33 - 48
PAULOS CM ET AL.: "The inducible costimulator (ICOS) is critical for the development of human Thl7 cells", SCI TRANSL MED, vol. 2, no. 55, 2010, pages 55ra78, XP002750842, DOI: 10.1126/scitranslmed.3000448
QUEEN ET AL., PROC. NATL ACAD SCI USA, vol. 86, 1989, pages 10029 - 10032
SCHMIDT MKAPP KOSWALD DMATTHIAS SWITTIG BZURLO A: "Pharmacokinetic and pharmacodynamic data of the immunotherapeutic TLR-9 agonist MGN 1703 from healthy volunteers and cancer patients", JOURNAL OF CLINICAL ONCOLOGY, vol. 33, no. 15, 2015, pages e14015
SHARPE AHFREEMAN GJ: "The B7-CD28 Superfamily", NAT. REV IMMUNOL, vol. 2, no. 2, 2002, pages 116 - 26, XP008018232, DOI: 10.1038/nri727
VAN EIJK LTPICKKERS PSMITS PBOUW MPVAN DER HOEVEN JG: "Severe vagal response after endotoxin administration in humans", INTENSIVE CARE MED., vol. 30, no. 12, December 2004 (2004-12-01), pages 2279 - 81, XP019323359, DOI: 10.1007/s00134-004-2477-0
WAKAMATSU E ET AL.: "Convergent and divergent effects of costimulatory molecules in conventional and regulatory CD4+ T cells", PROC NATL ACAD SCI USA, vol. 110, no. 3, 2013, pages 1023 - 8
WOLCHOK JDHOOS AO'DAY SWEBER JSHAMID OLEBBE C ET AL.: "Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria", CLIN CANCER RES., vol. 15, no. 23, 2009, pages 7412 - 20
YAO S ET AL.: "B7-H2 is a costimulatory ligand for CD28 in human", IMMUNITY, vol. 34, no. 5, 2011, pages 729 - 40, XP028218515, DOI: 10.1016/j.immuni.2011.03.014

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