WO2021046289A1 - Schéma posologique pour le traitement du cancer avec un anticorps agoniste anti-cos et de l'ipilimumab - Google Patents

Schéma posologique pour le traitement du cancer avec un anticorps agoniste anti-cos et de l'ipilimumab Download PDF

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WO2021046289A1
WO2021046289A1 PCT/US2020/049317 US2020049317W WO2021046289A1 WO 2021046289 A1 WO2021046289 A1 WO 2021046289A1 US 2020049317 W US2020049317 W US 2020049317W WO 2021046289 A1 WO2021046289 A1 WO 2021046289A1
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binding protein
seq
administered
dose
set forth
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PCT/US2020/049317
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Marc S. BALLAS
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Glaxosmithkline Intellectual Property Development Limited
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen

Definitions

  • the present invention relates to a method of treating cancer in a human.
  • the present invention relates to dosing of a combination of an agonist anti-ICOS antibody and ipilimumab.
  • BACKGROUND TO THE INVENTION Effective treatment of hyperproliferative disorders, including cancer, is a continuing goal in the oncology field.
  • 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.
  • 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.
  • the methods herein that relate to combining therapeutic approaches for enhancing anti-tumor immunity address this need.
  • a method of treating cancer in a human in need thereof comprising administering to the human an agonist ICOS binding protein or antigen binding portion thereof at a dose of about 0.08 mg to about 240 mg and administering to the human ipilimumab.
  • 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 administered at a dose of about 0.08 mg to about 240 mg and is administered with ipilimumab.
  • a combination of an agonist ICOS binding protein or antigen binding portion thereof and ipilimumab for use in treating cancer for use in treating cancer wherein the agonist ICOS binding protein or antigen binding portion thereof is administered at a dose of about 0.08 mg to about 240 mg.
  • use of an agonist ICOS binding protein or antigen binding portion thereof in the manufacture of a medicament for treating cancer wherein the agonist ICOS binding protein or antigen binding portion thereof is administered at a dose of about 0.08 mg to about 240 mg and is administered with ipilimumab.
  • a pharmaceutical kit comprising an ICOS binding protein or an antigen binding portion thereof at a concentration of 10 mg/ml and ipilimumab at a concentration of 5 mg/ml.
  • the agonist ICOS binding protein or antigen binding portion thereof comprises one or more of: CDRH1 as set forth in SEQ ID NO:1; CDRH2 as set forth in SEQ ID NO:2; CDRH3 as set forth in SEQ ID NO:3; CDRL1 as set forth in SEQ ID NO:4; CDRL2 as set forth in SEQ ID NO:5 and/or CDRL3 as set forth in SEQ ID NO:6 or a direct equivalent of each CDR wherein a direct equivalent has no more than two amino acid substitutions in said CDR.
  • the agonist ICOS binding protein or antigen binding portion thereof 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 agonist ICOS binding protein specifically binds to human ICOS.
  • the agonist ICOS binding protein is a monoclonal antibody.
  • agonist ICOS binding protein, combination, use, or pharmaceutical kit of the invention is a humanized or fully human monoclonal antibody.
  • the agonist ICOS binding protein comprises an hIgG4PE scaffold.
  • agonist ICOS binding protein, combination or use, any one of the invention is administered at a dose of 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.
  • agonist ICOS binding protein, combination or use of the invention is administered at a dose of about 24 mg.
  • agonist ICOS binding protein, acombination or use of the invention the agonist ICOS binding protein or antigen binding portion thereof is administered once every three weeks or every six weeks.
  • agonist ICOS binding protein, combination or use of the invention the agonist ICOS binding protein or antigen binding portion thereof and/or ipilimumab is administered via IV infusion.
  • the cancer is a solid tumor.
  • the cancer is selected from NSCLC, HNSCC, urothelial cancer, cervical cancer and melanoma.
  • agonist ICOS binding protein, combination or use of the invention the cancer is NSCLC.
  • agonist ICOS binding protein, combination or use of the invention comprises CDRH1 as set forth in SEQ ID NO:33; CDRH2 as set forth in SEQ ID NO:34; CDRH3 as set forth in SEQ ID NO:35; CDRL1 as set forth in SEQ ID NO:36; CDRL2 as set forth in SEQ ID NO:37 and CDRL3 as set forth in SEQ ID NO:38.
  • agonist ICOS binding protein, combination or use of the invention ipilimumab is administered at a dose of about 0.3 mg/kg to about 10 mg/kg.
  • agonist ICOS binding protein, combination or use of the invention ipilimumab is administered at a dose of about 1 mg/kg to about 3 mg/kg. In one embodiment of the method, agonist ICOS binding protein, combination or use of the invention, ipilimumab is administered once every three weeks or 6weeks. In another embodiment of the method, agonist ICOS binding protein, combination or use of the invention, ipilimumab is administered once every three weeks until toxicity, then every 6 weeks thereafter.
  • agonist ICOS binding protein In a further embodiment of the method, agonist ICOS binding protein, combination or use of the invention, the agonist ICOS binding protein is administered at a dose of 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 every three weeks, and ipilimumab is administered at a dose of about 0.3 mg/kg, about 1 mg/kg, about 3 mg/kg, about 6 mg/kg or about 10 mg/kg every three weeks.
  • the agonist ICOS binding protein or antigen binding portion thereof comprises CDRH1 as set forth in SEQ ID NO:1; CDRH2 as set forth in SEQ ID NO:2; CDRH3 as set forth in SEQ ID NO:3; CDRL1 as set forth in SEQ ID NO:4; CDRL2 as set forth in SEQ ID NO:5 and CDRL3 as set forth in SEQ ID NO:6, and wherein ipilimumab is administered at a dose of about 1 mg/kg or about 3 mg/kg every three weeks.
  • the agonist ICOS binding protein or antigen binding portion thereof comprises CDRH1 as set forth in SEQ ID NO:1; CDRH2 as set forth in SEQ ID NO:2; CDRH3 as set forth in SEQ ID NO:3; CDRL1 as set forth in SEQ ID NO:4; CDRL2 as set forth in SEQ ID NO:5 and CDRL3 as set forth in SEQ ID NO:6, and wherein ipilimumab is administered at a dose of about 1 mg/kg or about 3 mg/kg every three weeks; and wherein the agonist ICOS binding protein or antigen binding portion thereof is administered first as an IV infusion and ipilimumab is administered as an IV infusion beginning at least 30 minus and no more than 2 hours following the end of the administration of the agonist ICOS binding protein or antigen binding portion thereof.
  • agonist ICOS binding protein, combination or use the invention comprises administration of a chemotherapeutic agent.
  • agonist ICOS binding protein, combination or use of the invention the agonist ICOS binding protein or antigen binding portion thereof and ipilimumab is administered concurrently and/or sequentially.
  • the embodiments described in the applicaiton relate to the method of treatment, the agonist ICOS binding protein or antigen binding portion thereof for use, combination for use, use of the agonist ICOS binding protein or antigen binding portion thereof in the manufacture of a medicament, the composition and the pharmaceutical kit of the invention. DESCRIPTION OF DRAWINGS/FIGURES FIG.
  • FIGS. 2A-2B are plots showing duration of H2L5 IgG4PE monotherapy treatment: individual patient data.
  • FIG. 2A shows monotherapy dose escalation cohort.
  • FIG. 2B shows PK/PD cohort.
  • FIG. 3A-3D are plots showing PK and receptor occupancy.
  • FIG 3A shows dose-proportional PK from 0.01 mg/kg to 3 mg/kg;
  • FIG. 3B shows peak receptor occupancy corresponding to maximum plasma concentration; similar relationship for CD8+ receptor occupancy (data not shown).
  • FIG. 3C shows CD4 + RO with H2L5 IgG4PE 0.3 mg/kg and 1.0 mg/kg monotherapy (Part 1A)
  • FIG. 3D is a plot showing receptor occupancy (RO) H2L5 IgG4PE concentration.
  • FIGS. 4A-4C show PK/PD and immunofluorescence data characterising immune phenotype of TIL.
  • FIG. 4A shows cytotoxic T cell to Treg ratio across H2L5 IgG4PE concentrations.
  • FIG. 4B shows MultiOmyx TM dose-response curves.
  • FIG 4C shows ratio of cytotoxic T cell proliferation:Treg proliferation.
  • 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.
  • 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.
  • 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 IgG1, 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”, “binding protein”, “antigen binding agent” and “binding agent” are used interchangeably herein.
  • agonist ICOS binding proteins refers to a site on an antigen binding protein that is capable of specifically binding to an antigen, this may be a single variable domain, or it may be paired VH/VL domains as can be found on a standard antibody.
  • Single-chain Fv (scFv) domains can also provide antigen-binding sites.
  • antibody is used herein in the broadest sense to refer to molecules comprising 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.
  • a “chimeric antibody” refers to a type of engineered antibody that 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. Bio/Technology, 9:421 (1991)).
  • a suitable human acceptor antibody may be one selected from a conventional database, e.g.
  • 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.
  • 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.
  • An intact antibody is composed of two identical heavy chains (HCs) and two identical light chains (LCs) linked by covalent disulphide bonds.
  • This H2L2 structure folds to form three functional domains comprising two antigen-binding fragments, known as ‘Fab’ fragments, and a ‘Fc’ crystallisable fragment.
  • the Fab fragment is composed of the variable domain at the amino-terminus, variable heavy (VH) or variable light (VL), and the constant domain at the carboxyl terminus, CH1 (heavy) and CL (light).
  • the Fc fragment is composed of two domains formed by dimerization of paired CH2 and CH3 regions. The Fc may elicit effector functions by binding to receptors on immune cells or by binding C1q, the first component of the classical complement pathway.
  • the five classes of antibodies IgM, IgA, IgG, IgE and IgD are defined by distinct heavy chain amino acid sequences which are called ⁇ , a, g, e and d respectively, each heavy chain can pair with either a K or l light chain.
  • the majority of antibodies in the serum belong to the IgG class, there are four isotypes of human IgG, IgG1, IgG2, IgG3 and IgG4, the sequences of which differ mainly in their hinge region.
  • Fully human antibodies can be obtained using a variety of methods, for example using yeast- based libraries or transgenic animals (e.g. mice) which are capable of producing repertoires of human antibodies.
  • Yeast presenting human antibodies on their surface which bind to an antigen of interest can be selected using FACS (Fluorescence-Activated Cell Sorting) based methods or by capture on beads using labelled antigens.
  • Transgenic animals that have been modified to express human immunoglobulin genes can be immunised with an antigen of interest and antigen-specific human antibodies isolated using B-cell sorting techniques. Human antibodies produced using these techniques can then be characterised for desired properties such as affinity, developability and selectivity.
  • domain refers to a folded polypeptide structure that retains its tertiary structure independent of the rest of the polypeptide.
  • 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 V H , V HH and V L 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” 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 DABS.
  • 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.
  • 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.
  • variable domain sequences and variable domain regions within full length antigen binding sequences are numbered according to the Kabat numbering convention.
  • CDR the terms “CDR”, “CDRL1”, “CDRL2”, “CDRL3”, “CDRH1”, “CDRH2”, “CDRH3” used in the Examples follow the Kabat numbering convention.
  • Kabat et al. Sequences of Proteins of Immunological Interest 5th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1991). It will be apparent to those skilled in the art that there are alternative numbering conventions for amino acid residues in variable domain sequences and full length antibody sequences.
  • CDR sequences There are also alternative numbering conventions for CDR sequences, for example those set out in Chothia et al. (1989) Nature 342: 877-883.
  • the structure and protein folding of the antigen binding protein may mean that other residues are considered part of the CDR sequence and would be understood to be so by a skilled person.
  • Other numbering conventions for CDR sequences available to a skilled person include “AbM” (University of Bath) and “contact” (University College London) methods.
  • the minimum overlapping region using at least two of the Kabat, Chothia, AbM and contact methods can be determined to provide the “minimum binding unit”.
  • the minimum binding unit may be a sub-portion of a CDR.
  • 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.
  • 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. It will be appreciated that each of CDR H1, H2, H3, L1, 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 (referred herein also as a direct equivalent), for example as shown in Table 1 below.
  • Table 1 The VH or VL (or HC or LC) sequence may be a variant sequence with up to 10 amino acid substitutions, additions or deletions.
  • the variant sequence may have up to 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid substitution(s), addition(s) or deletion(s).
  • the sequence variation may exclude one or more or all of the CDRs, for example the CDRs are the same as the VH or VL (or HC or LC) sequence and the variation is in the remaining portion of the VH or VL (or HC or LC) sequence, so that the CDR sequences are fixed and intact.
  • the variation is a substitution, particularly a conservative substitution, for example as shown in Table 1.
  • Percent identity between a query amino acid sequence and a subject amino acid sequence is the “Identities” value, expressed as a percentage, that is calculated using a suitable algorithm or software, such as BLASTP, FASTA, DNASTAR Lasergene, GeneDoc, Bioedit, EMBOSS needle or EMBOSS infoalign, over the entire length of the query sequence after a pair-wise global sequence alignment has been performed using a suitable algorithm/software such as BLASTP, FASTA, ClustalW, MUSCLE, MAFFT, EMBOSS Needle, T-Coffee, and DNASTAR Lasergene.
  • a query amino acid sequence may be described by an amino acid sequence identified in one or more claims herein.
  • the query sequence may be 100% identical to the subject sequence, or it may include up to a certain integer number of amino acid or nucleotide alterations as compared to the subject sequence such that the % identity is less than 100%.
  • the query sequence is at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to the subject sequence.
  • Such alterations include at least one amino acid deletion, substitution (including conservative and non-conservative substitution), or insertion, and wherein said alterations may occur at the amino- or carboxy-terminal positions of the query sequence or anywhere between those terminal positions, interspersed either individually among the amino acids or nucleotides in the query sequence or in one or more contiguous groups within the query sequence.
  • the % identity may be determined across the entire length of the query sequence, including the CDRs.
  • the % identity may exclude one or more or all of the CDRs, for example all of the CDRs are 100% identical to the subject sequence and the % identity variation is in the remaining portion of the query sequence, e.g. the framework sequence, so that the CDR sequences are fixed and intact.
  • the variant sequence substantially retains the biological characteristics of the unmodified protein, such as an agonist for ICOS.
  • 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.
  • 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 IgG1, IgG2, IgG3, IgG4 or IgG4PE.
  • the scaffold may be IgG1.
  • the scaffold may consist of, or comprise, the Fc region of an antibody, or is a part thereof.
  • the subclass of an antibody in part 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
  • hIgG1 antibodies have a relatively long half life, are very effective at fixing complement, and they bind to both FcgRI and FcgRII.
  • human IgG4 antibodies have a shorter half life, do not fix complement and have a lower affinity for the FcRs.
  • Replacement of serine 228 with a proline (S228P) in the Fc region of IgG4 reduces heterogeneity observed with hIgG4 and extends the serum half life (Kabat et al. “Sequences of proteins of immunological interest” 5.sup.th Edition (1991); Angal et al. Mol Immunol 30(1): 105-8 (1993)).
  • the ICOS antibody is an IgG4 isotype or a variant thereof.
  • the ICOS antibody comprises an IgG4 Fc region comprising the replacement S228P and L235E or a functional variant thereof.
  • Such an antibody may have the designation IgG4PE.
  • the agonist ICOS binding protein is H2L5 IgG4PE.
  • 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.
  • Affinity also referred to as “binding affinity”, is the strength of binding at a single interaction site, i.e. of one molecule, e.g. an antigen binding protein of the invention, to another molecule, e.g. its target antigen, at a single binding site.
  • binding affinity of an antigen binding protein to its target may be determined by equilibrium methods (e.g.
  • ELISA enzyme-linked immunoabsorbent assay
  • RIA radioimmunoassay
  • kinetics e.g. BIACORE analysis
  • Avidity also referred to as functional affinity, is the cumulative strength of binding at multiple interaction sites, e.g. the sum total of the strength of binding of two molecules (or more, e.g. in the case of a bispecific or multispecific molecule) to one another at multiple sites, e.g. taking into account the valency of the interaction.
  • 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 an aspect of 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 (e.g. dostarlimab, OPDIVO/nivolumab, KEYTRUDA/pembrolizumab and LIBTAYO/cemiplimab), anti-CTLA-4 antibodies and anti-ICOS antibodies.
  • agonist refers to an antigen binding protein including, but not limited to, an antibody, that is capable of activating the antigen to which it binds to induce a full or partial antigen-mediated response that is above the response measured in the absence of the antigen binding protein.
  • agonistic responses include but are not limited to transduction of a survival, growth, proliferation, differentiation and/or maturation signal.
  • the agonist 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.
  • the term “antagonist” refers to an antigen binding protein including, but not limited to, an antibody, that is capable of fully or partially inhibiting the biological activity of the antigen to which it binds for example by fully or partially blocking binding or neutralising activity.
  • the antagonist 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 PD-1 binding protein is an antagonist PD-1 binding protein.
  • 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 as used herein 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.
  • a cell or cell free expression system e.g. reticulocyte lysate
  • 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.
  • mammalian gene promoters such as human Ig gene promoters.
  • prokaryotic expression vectors such as T7 promoter driven vectors, e.g. pET41, lactose promoter driven vectors and arabinose gene promoter driven vectors.
  • Those of ordinary skill in the art will recognize many other suitable expression vectors and expression systems.
  • the term “recombinant host cell” as used herein 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-1, COS- 7, HEK293, BHK21, CHO, BSC-1, 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.
  • the term "effective dose” means that dose of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective dose means any dose that, as compared to a corresponding subject who has not received such dose, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • doses effective to enhance normal physiological function are generally determined empirically and may be dependent on factors, such as the age, weight, and health status of the patient and disease or disorder to be treated. Such factors are within the purview of the attending physician. Ranges provided herein, of any type, include all values within a particular range described and values about an endpoint for a particular range.
  • therapeutic agents refers to therepeutic agents of the invention.
  • the therapeutic agents are agonist ICOS binding proteins, ipilimumab and immunomdulatory agents.
  • one or more additional agents may be administered in addition to agonist ICOS binding proteins and ipilimumab.
  • additional agents include, but are not limited to additional immunomodulators and chemotherapeutic agents.
  • additional immunomodulators such as a PD1 binding protein or antigen binding portion thereof or a PDL-1 binding protein or antigen binding portion thereof.
  • references to “therapeutic agents” include embodiments where the two therapeutic agents are administered in any temporal order, such as concurrently or sequentially. The terms concurrent and sequential administration of therapeutic agents are well understood in the art.
  • the individual therapeutic agents, and pharmaceutical compositions comprising such therapeutic agents may be administered together or separately. When administered separately, this may occur concurrently or sequentially in any order (by the same or by different routes of administration). Such sequential administration may be close in time or remote in time.
  • the dose of a therapeutic agents or pharmaceutically acceptable salt thereof and the further therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration of the therapeutic agents may be advantageous over the individual therapeutic agents in that the combination of the therapeutic agents may provide one or more of the following improved properties when compared to the individual administration of a single therapeutic agent alone: i) a greater anticancer effect than the most active single agent, ii) synergistic or highly synergistic anticancer activity, iii) a dosing protocol that provides enhanced anticancer activity with reduced side effect profile, iv) a reduction in the toxic effect profile, v) an increase in the therapeutic window, and/or vi) an increase in the bioavailability of one or both of the therapeutic agents.
  • each therapeutic agent is formulated into its own pharmaceutical composition and each of the pharmaceutical compositions are administered to treat cancer.
  • each of the pharmaceutical compositions may have the same or different carriers, diluents or excipients.
  • a first pharmaceutical composition contains an agonist ICOS binding protein
  • a second pharmaceutical composition contains ipilimumab
  • the first and second pharmaceutical compositions are both administered to treat cancer.
  • the combination comprising an agonist ICOS binding protein and ipilimumab is formulated together into a single pharmaceutical composition and administered to treat cancer.
  • a single pharmaceutical composition contains both an agonist ICOS binding protein and ipilimumab and is administered as a single pharmaceutical composition to treat cancer.
  • Antigen Binding Proteins, Antibodies that bind ICOS, and Ipilimumab Agents directed to ICOS in any of the aspects or embodiments of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to ICOS.
  • the mAb to ICOS specifically binds to human ICOS.
  • the agonist ICOS binding protein is a monoclonal antibody or antigen binding fragment thereof.
  • the mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region.
  • the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region.
  • the antigen binding fragment may be selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.
  • ICOS means any Inducible T-cell costimulator protein.
  • Pseudonyms for ICOS include AILIM; CD278; CVID1, JTT-1 or JTT-2, MGC39850, or 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 proliferation.
  • the amino acid sequence of human ICOS (isoform 2) (Accession No.: UniProtKB - Q9Y6W8-2) is shown below as SEQ ID NO:11.
  • VCILGCILICWLTKKM SEQ ID NO:11
  • the amino acid sequence of human ICOS isoform 1 (Accession No.: UniProtKB - Q9Y6W8- 1) is shown below as SEQ ID NO:12.
  • 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 et al. “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 na ⁇ ve TH1 and TH2 effector T cell populations (Paulos et al. “The inducible costimulator (ICOS) is critical for the development of human Th17 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 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 regulates the production of both TH1 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)).
  • agent directed to ICOS any chemical compound or biological molecule capable of binding to ICOS.
  • the agent directed to ICOS is an agonist ICOS binding protein or antigen binding portion thereof.
  • the term “ICOS binding protein” as used herein refers to a protein that binds to ICOS, including an antibody or an antigen binding fragment thereof, or engineered molecules that function in similar ways to antibodies that are capable of binding to ICOS.
  • the antibody is a monoclonal antibody.
  • the ICOS is human ICOS.
  • the term “ICOS binding protein” can be used interchangeably with “ICOS binding protein”, “ICOS binding agent”, “ICOS antigen binding protein” or “ICOS antigen binding agent”.
  • anti-ICOS antibodies and/or ICOS antigen binding proteins would be considered ICOS binding proteins.
  • This definition does not include the natural cognate ligand or receptor.
  • References to ICOS binding proteins, in particular anti-ICOS antibodies, includes antigen binding portions or fragments thereof.
  • 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 agonist ICOS binding proteins of the present invention comprise any one or a combination of the following CDRs: CDRH1: DYAMH (SEQ ID NO:1) CDRH2: LISIYSDHTNYNQKFQG (SEQ ID NO:2) CDRH3: NNYGNYGWYFDV (SEQ ID NO:3) CDRL1: SASSSVSYMH (SEQ ID NO:4) CDRL2: DTSKLAS (SEQ ID NO:5) CDRL3: FQGSGYPYT (SEQ ID NO:6)
  • the agonist ICOS binding protein comprises a heavy chain variable region CDR1 (“CDRH1”) comprising an amino acid sequence with one or two amino acid variation(s) (“CDR variant”) to the amino acid sequence set forth in SEQ ID NO:1.
  • the agonist ICOS binding protein comprises a heavy chain variable region CDR2 (“CDRH2”) comprising an amino acid sequence with five or fewer, such as four or fewer, three or fewer, two or fewer, or one amino acid variation(s) (“CDR variant”) to the amino acid sequence set forth in SEQ ID NO:2.
  • CDRH2 comprises an amino acid sequence with one or two amino acid variation(s) to the amino acid sequence set forth in SEQ ID NO:2.
  • the agonist ICOS binding protein comprises a heavy chain variable region CDR3 (“CDRH3”) comprising an amino acid sequence with one or two amino acid variation(s) (“CDR variant”) to the amino acid sequence set forth in SEQ ID NO:3.
  • the agonist ICOS binding protein comprises a light chain variable region CDR1 (“CDRL1”) comprising an amino acid sequence with three or fewer, such as one or two amino acid variation(s) (“CDR variant”) to the amino acid sequence set forth in SEQ ID NO:4.
  • the agonist ICOS binding protein comprises a light chain variable region CDR2 (“CDRL2”) comprising an amino acid sequence with one or two amino acid variation(s) (“CDR variant”) to the amino acid sequence set forth in SEQ ID NO:5.
  • the agonist ICOS binding protein comprises a light chain variable region CDR3 (“CDRL3”) comprising an amino acid sequence with three or fewer, such as one or two amino acid variation(s) (“CDR variant”) to the amino acid sequence set forth in SEQ ID NO:6.
  • CDRL3 light chain variable region CDR3
  • CDR variant amino acid variation(s)
  • the agonist ICOS binding protein comprises a CDRH1 comprising an amino acid sequence with up to one amino acid variation to the amino acid sequence set forth in SEQ ID NO:1; a CDRH2 comprising an amino acid sequence with up to five amino acid variations to the amino acid sequence set forth in SEQ ID NO:2; a CDRH3 comprising an amino acid sequence with up to one amino acid variation to the amino acid sequence set forth in SEQ ID NO:3; a CDRL1 comprising an amino acid sequence with up to three amino acid variations to the amino acid sequence set forth in SEQ ID NO:4; a CDRL2 comprising an amino acid sequence with up to one amino acid variation to the amino acid sequence set forth in SEQ ID NO:5; and/or a CDRL3 comprising an amino acid sequence with up to three amino acid variations to the amino acid sequence set forth in SEQ ID NO:6.
  • the agonist ICOS binding protein binding protein comprises any one or a combination of the CDRs of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.
  • the agonist ICOS binding protein or antigen binding portion thereof comprises one or more of : CDRH1 as set forth in SEQ ID NO:1; CDRH2 as set forth in SEQ ID NO:2; CDRH3 as set forth in SEQ ID NO:3; CDRL1 as set forth in SEQ ID NO:4; CDRL2 as set forth in SEQ ID NO:5 and/or CDRL3 as set forth in SEQ ID NO:6 or a direct equivalent of each CDR wherein a direct equivalent has no more than two amino acid substitutions in said CDR.
  • the ICOS binding protein binding protein comprises the CDRs of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.
  • the agonist ICOS binding protein comprises CDRH1 (SEQ ID NO:1), CDRH2 (SEQ ID NO:2), and CDRH3 (SEQ ID NO:3) in the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:7.
  • the agonist ICOS binding proteins of the present invention comprising the humanized heavy chain variable region set forth in SEQ ID NO:7 are designated as “H2.”
  • 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 agonist 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.
  • 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 anti-ICOS antibodies of the present invention comprise a heavy chain variable region as set forth in SEQ ID NO:7.
  • the agonist ICOS binding protein comprises a heavy chain variable region (“VH”) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:7.
  • the VH comprises an amino acid sequence with at least one amino acid variation to the amino acid sequence set forth in SEQ ID NO:7, such as between 1 and 5, such as between 1 and 3, in particular up to 2 amino acid variations to the amino acid sequence set forth in SEQ ID NO:7.
  • the agonist ICOS binding protein comprises CDRL1 (SEQ ID NO:4), CDRL2 (SEQ ID NO:5), and CDRL3 (SEQ ID NO:6) in the light chain variable region having the amino acid sequence set forth in SEQ ID NO:8.
  • Agonist 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 agonist 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 agonist 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 agonist 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.
  • the agonist ICOS binding protein comprises a light chain variable region (“VL”) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:8.
  • the VL comprises an amino acid sequence with at least one amino acid variation to the amino acid sequence set forth in SEQ ID NO:8, such as between 1 and 5, such as between 1 and 3, in particular up to 2 amino acid variations to the amino acid sequence set forth in SEQ ID NO:8.
  • the anti-ICOS antibody comprises a light chain variable region having at least 90% sequence identity to SEQ ID NO:8. In one embodiment, the anti-ICOS antibody comprises a light chain variable region as set forth in SEQ ID NO:8.
  • the agonist 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.
  • the agonist 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 the agonist ICOS binding protein specifically binds to human ICOS.
  • the agonist ICOS binding protein comprises a VH with the amino acid sequence set forth in SEQ ID NO:7; and a VL with the amino acid sequence set forth in SEQ ID NO:8.
  • the agonist ICOS binding protein comprises a VH comprising an amino acid sequence of SEQ ID NO:7 and a VL comprising an amino acid sequence of SEQ ID NO:8.
  • the agonist ICOS binding protein specifically binds to human ICOS.
  • the agonist ICOS binding protein comprises a VH comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:7; and a VL comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:8.
  • the agonist 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 V L domain comprising an amino acid sequence at least 90% identical to the amino acid sequence as set forth in SEQ ID NO:8, and further comprises any one or a combination of the CDRs of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.
  • the agonist ICOS binding protein is a humanized monoclonal antibody comprising a heavy chain (HC) amino acid sequence having at least 90%, 91%, 92,%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:9.
  • the HC comprises an amino acid sequence with at least one amino acid variation to the amino acid sequence set forth in SEQ ID NO:9, such as between 1 and 10, such as between 1 and 7, in particular up to 6 amino acid variations to the amino acid sequence set forth in SEQ ID NO:9.
  • the HC comprises one, two, three, four, five, six or seven amino acid variations to the amino acid sequence set forth in SEQ ID NO:9.
  • the agonist ICOS binding protein is a humanized monoclonal antibody comprising a light chain (LC) amino acid sequence having at least 90%, 91%, 92,%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:10.
  • the LC comprises an amino acid sequence with at least one amino acid variation to the amino acid sequence set forth in SEQ ID NO:10, such as between 1 and 10, such as between 1 and 5, in particular up to 3 amino acid variations to the amino acid sequence set forth in SEQ ID NO:10.
  • the LC comprises one, two or three amino acid variations to the amino acid sequence set forth in SEQ ID NO:10.
  • the agonist ICOS binding protein comprises a HC comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:9; and a LC comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:10.
  • the antibody is an antibody with a heavy chain at least about 90% identical to the heavy chain amino acid sequence of SEQ ID NO:9 and/or with a light chain at least about 90% identical to the light chain amino acid sequence of SEQ ID NO:10.
  • the agonist ICOS binding protein comprises a heavy chain amino acid sequence at least about 90% identical to the amino acid sequence of SEQ ID NO:9 and/or a light chain amino acid sequence at least about 90% identical to the amino acid sequence of SEQ ID NO:10.
  • the agonist ICOS binding protein comprises a heavy chain sequence of SEQ ID NO:9 and a light chain sequence of SEQ ID NO:10.
  • an agonist ICOS binding protein comprising a heavy chain constant region that has reduced ADCC and/or complement activation or effector functionality as compared to IgG1.
  • the IgG1 is wild type (WT) IgG1.
  • the heavy chain constant region may comprise a naturally disabled constant region of IgG2 or IgG4 isotype or variant thereof, or a mutated or disabled IgG1 constant region.
  • the agonist ICOS binding protein comprises an IgG4 isotype or a variant thereof.
  • the agonist ICOS binding protein comprises an IgG4 Fc region comprising the amino acid substitutions S228P and L235E or functional equivalents thereof.
  • the agonist ICOS binding protein comprises an IgG4 Fc region comprising amino acid subsitutions S229P and L236E.
  • IgG4PE an agonist ICOS binding protein having the heavy chain variable region H2 and the light chain variable region L5 and an IgG4PE Fc region will be designated as H2L5 IgG4PE or synonymously as H2L5 hIgG4PE.
  • Antibodies to ICOS and methods of using in the treatment of disease are described, for instance, in WO2012131004, US20110243929, and US20160215059. US20160215059 is incorporated by reference herein.
  • CDRs for murine antibodies to human ICOS having agonist activity are shown in PCT/EP2012/055735 (WO2012131004).
  • Antibodies to ICOS are also disclosed in WO2008137915, WO2010056804, EP1374902, EP1374901, and EP1125585.
  • Agonist antibodies to ICOS or ICOS binding proteins are disclosed in WO2012/13004, WO2014033327, WO2016120789, US20160215059, and US20160304610.
  • Exemplary antibodies in US20160304610 include 37A10S713. Sequences of 37A10S713 are reproduced below as SEQ ID NOS:13-20.
  • the agonist ICOS binding protein is vopratelimab.
  • the agonist ICOS binding protein is JTX-2011.
  • Exemplary antibodies in US2018/0289790 include ICOS.33 IgG1f S267E. Sequences of ICOS.33 IgG1f S267E are reproduced below as SEQ ID NOS:21-22.
  • ICOS.33 IgG1f S267E light chain variable domain In one embodiment, the agonist ICOS binding protein is BMS-986226.
  • Exemplary antibodies in WO2018/029474 include STIM003. Sequences of STIM003 are reproduced below as SEQ ID NOS: 23-24.
  • STIM003 heavy chain variable domain STIM003 light chain variable domain: Q ( Q )
  • the agonist ICOS binding protein is KY1044.
  • Exemplary antibodies in WO2018/045110 include XENP23104. Sequences of the ICOS binding Fab side ([ICOS]_H0.66_L0) of XENP23104 are reproduced below as SEQ ID NOS:25-32.
  • XENP23104 [ICOS]_H0.66_L0 VH CDR1 GYYMH (SEQ ID NO:26)
  • XENP23104 [ICOS]_H0.66_L0 VH CDR2 WINPHSGETIYAQKFQG (SEQ ID NO:27)
  • XENP23104 [ICOS]_H0.66_L0 VH CDR3 TYYYDTSGYYHDAFDV (SEQ ID NO:28)
  • XENP23104 [ICOS] H0.66 L0 light chain variable domain correspond to the positions of CDRs).
  • 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).
  • Ipilimumab (YERVOY; 10D1; BMS734016; MDX 101; MDX-010; MDX-CTLA-4; MDX-CTLA4) is a recombinant, human monoclonal IgG1 antibody that binds to CTLA-4.
  • CTLA-4 is a negative regulator of T-cell activity.
  • Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86.
  • Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T cell responsiveness, including the anti-tumor immune response Ipilimumab has been administered as both monotherapy and combination therapy.
  • a randomized trial in patients with unresectable or metastatic melanoma, ipilimumab 3 mg/kg was given as a single agent or in combination with gp100, a peptide vaccine.
  • the best overall response rate (BORR) as assessed by the investigator was 5.7% (95% CI: 3.7%, 8.4%) in the ipilimumab plus gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in the ipilimumab arm, and 1.5% (95% CI: 0.2%, 5.2%) in the gp100 arm.
  • the median duration of response was 11.5 months in the ipilimumab plus gp100 arm and has not been reached in the ipilimumab or gp100 arm.
  • ipilimumab 10 mg/kg was given as a single agent.
  • the median RFS was 26 months (95% CI: 19, 39) and for placebo was 17 months (95% CI: 13, 22).
  • CHECKMATE-214 NCT02231749
  • ipilimumab 1 mg/kg was administered in combination with nivolumab 3 mg/kg in previously untreated patients with advanced renal cell carcinoma.
  • the proportion of patients with a DOR 36 months was 83% for ipilimumab plus nivolumab and 89% for nivolumab monotherapy.
  • CHECKMATE-040 NCT01658878
  • a multicenter, multiple cohort, open-label trial conducted in patients with hepatocellular carcinoma who progressed on or were intolerant to sorafenib were given ipilimumab 3 mg/kg, administered in combination with nivolumab.
  • the ORR for the ipilimumab plus nivolumab cohort was 33% while the proportion of patients with a DOR 36 months was 88%. Ipilimumab is described for example in US Patent Application Publication No.
  • the CTLA-4 binding protein or antigen binding portion thereof comprises any one or a combination of the following CDRs: CDRH1: SYTMH (SEQ ID NO:33) CDRH2: FISYDGNNKYYADSVKG (SEQ ID NO:34) CDRH3: TGWLGPFDY (SEQ ID NO:35) CDRL1: RASQSVGSSYLA (SEQ ID NO:36) CDRL2: GAFSRAT (SEQ ID NO:37) CDRL3: QQYGSSPWT (SEQ ID NO:38)
  • the CTLA-4 binding protein or antigen binding portion thereof comprises a heavy chain variable region CDR1 (“CDRH1”) comprising an amino acid sequence with one or two amino acid variation(s) (“CDR variant”) to the amino acid sequence set forth in SEQ ID NO:33.
  • the CTLA-4 binding protein or antigen binding portion thereof comprises a heavy chain variable region CDR2 (“CDRH2”) comprising an amino acid sequence with five or fewer, such as four or fewer, three or fewer, two or fewer, or one amino acid variation(s) (“CDR variant”) to the amino acid sequence set forth in SEQ ID NO:34.
  • CDRH2 comprises an amino acid sequence with one or two amino acid variation(s) to the amino acid sequence set forth in SEQ ID NO:34.
  • the CTLA-4 binding protein or antigen binding portion thereof comprises a heavy chain variable region CDR3 (“CDRH3”) comprising an amino acid sequence with one or two amino acid variation(s) (“CDR variant”) to the amino acid sequence set forth in SEQ ID NO:35.
  • CDRH3 heavy chain variable region CDR3
  • CDR variant amino acid variation(s)
  • CDRL1 light chain variable region CDR1
  • CDRL1 light chain variable region CDR1
  • the CTLA-4 binding protein or antigen binding portion thereof comprises a light chain variable region CDR2 (“CDRL2”) comprising an amino acid sequence with one or two amino acid variation(s) (“CDR variant”) to the amino acid sequence set forth in SEQ ID NO:37.
  • the CTLA-4 binding protein or antigen binding portion thereof comprises a light chain variable region CDR3 (“CDRL3”) comprising an amino acid sequence with three or fewer, such as one or two amino acid variation(s) (“CDR variant”) to the amino acid sequence set forth in SEQ ID NO:38.
  • the CTLA-4 binding protein or antigen binding portion thereof comprises a CDRH1 comprising an amino acid sequence with up to one amino acid variation to the amino acid sequence set forth in SEQ ID NO:33; a CDRH2 comprising an amino acid sequence with up to five amino acid variations to the amino acid sequence set forth in SEQ ID NO:34; a CDRH3 comprising an amino acid sequence with up to one amino acid variation to the amino acid sequence set forth in SEQ ID NO:35; a CDRL1 comprising an amino acid sequence with up to three amino acid variations to the amino acid sequence set forth in SEQ ID NO:36; a CDRL2 comprising an amino acid sequence with up to one amino acid variation to the amino acid sequence set forth in SEQ ID NO:37; and/or a CDRL3 comprising an amino acid sequence with up to three amino acid variations to the amino acid sequence set forth in SEQ ID NO:38.
  • a CDRH1 comprising an amino acid sequence with up to one amino acid variation to the amino acid sequence set forth in SEQ ID NO:33
  • the CTLA-4 binding protein or antigen binding portion thereof comprises any one or a combination of the CDRs of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38.
  • the CTLA-4 binding protein or antigen binding portion thereof comprises one or more of : CDRH1 as set forth in SEQ ID NO:33; CDRH2 as set forth in SEQ ID NO:34; CDRH3 as set forth in SEQ ID NO:35; CDRL1 as set forth in SEQ ID NO:36; CDRL2 as set forth in SEQ ID NO:37 and/or CDRL3 as set forth in SEQ ID NO:38 or a direct equivalent of each CDR wherein a direct equivalent has no more than two amino acid substitutions in said CDR.
  • the CTLA-4 binding protein or antigen binding portion thereof comprises the CDRs of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38.
  • the CTLA-4 binding protein comprises CDRH1 (SEQ ID NO:33), CDRH2 (SEQ ID NO:34), and CDRH3 (SEQ ID NO:35) in the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO:39.
  • the CTLA-4 binding proteins comprise a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:39.
  • the CTLA-4 binding proteins 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:39.
  • the CTLA-4 binding proteins comprise a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:39.
  • the CTLA-4 binding protein or antigen binding portion thereof comprises a heavy chain variable region as set forth in SEQ ID NO:39.
  • CTLA-4 binding protein heavy chain (VH) variable region comprises a heavy chain variable region (“VH”) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:39.
  • VH comprises an amino acid sequence with at least one amino acid variation to the amino acid sequence set forth in SEQ ID NO:39, such as between 1 and 5, such as between 1 and 3, in particular up to 2 amino acid variations to the amino acid sequence set forth in SEQ ID NO:39.
  • the CTLA-4 binding protein comprises CDRL1 (SEQ ID NO:42), CDRL2 (SEQ ID NO:43), and CDRL3 (SEQ ID NO:44) in the light chain variable region having the amino acid sequence set forth in SEQ ID NO:40.
  • the CTLA-4 binding proteins comprise a light chain variable region having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:40.
  • the CTLA-4 binding proteins 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:40.
  • the CTLA-4 binding protein or antigen binding portion thereof comprises a heavy chain variable region as set forth in SEQ ID NO:40.
  • CTLA-4 binding light chain (VL) variable region correspond to the positions of CDRs).
  • the CTLA-4 binding protein comprises a light chain variable region (“VL”) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:40.
  • the VL comprises an amino acid sequence with at least one amino acid variation to the amino acid sequence set forth in SEQ ID NO:40, such as between 1 and 5, such as between 1 and 3, in particular up to 2 amino acid variations to the amino acid sequence set forth in SEQ ID NO:8.
  • the anti-CTLA-4 antibody comprises a light chain variable region having at least 90% sequence identity to SEQ ID NO:40. In one embodiment, the anti-CTLA-4 antibody comprises a light chain variable region as set forth in SEQ ID NO:40.
  • the CTLA-4 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:39 and/or a V L domain comprising an amino acid sequence at least 90% identical to the amino acid sequence as set forth in SEQ ID NO:40. In one embodiment, the CTLA-4 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:39 and/or a V L domain comprising an amino acid sequence at least 90% identical to the amino acid sequence as set forth in SEQ ID NO:40, wherein the CTLA-4 binding protein specifically binds to human CTLA-4.
  • the CTLA-4 binding protein comprises a VH with the amino acid sequence set forth in SEQ ID NO:39; and a VL with the amino acid sequence set forth in SEQ ID NO:40.
  • the CTLA-4 binding protein comprises a VH comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:39; and a VL comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:40.
  • the CTLA-4 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:39 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:40, and further comprises any one or a combination of the CDRs of SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38.
  • the CTLA-4 binding protein is a humanized monoclonal antibody comprising a heavy chain (HC) amino acid sequence having at least 90%, 91%, 92,%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:41.
  • the CTLA-4 binding protein or antigen binding portion thereof comprises a heavy chain as set forth in SEQ ID NO:41.
  • the HC comprises an amino acid sequence with at least one amino acid variation to the amino acid sequence set forth in SEQ ID NO:41, such as between 1 and 10, such as between 1 and 7, in particular up to 6 amino acid variations to the amino acid sequence set forth in SEQ ID NO:41.
  • the HC comprises one, two, three, four, five, six or seven amino acid variations to the amino acid sequence set forth in SEQ ID NO:41.
  • the CTLA-4 binding protein is a humanized monoclonal antibody comprising a light chain (LC) amino acid sequence having at least 90%, 91%, 92,%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:42.
  • the CTLA-4 binding protein or antigen binding portion thereof comprises a heavy chain variable region as set forth in SEQ ID NO:42.
  • CTLA-4 binding protein light chain comprises an amino acid sequence with at least one amino acid variation to the amino acid sequence set forth in SEQ ID NO:42, such as between 1 and 10, such as between 1 and 5, in particular up to 3 amino acid variations to the amino acid sequence set forth in SEQ ID NO:42.
  • the LC comprises one, two or three amino acid variations to the amino acid sequence set forth in SEQ ID NO:42.
  • the CTLA-4 binding protein comprises a HC comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:41; and a LC comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO:42.
  • the antibody is an antibody with a heavy chain at least about 90% identical to the heavy chain amino acid sequence of SEQ ID NO:41 and/or with a light chain at least about 90% identical to the light chain amino acid sequence of SEQ ID NO:42.
  • the CTLA-4 binding protein comprises a heavy chain amino acid sequence at least about 90% identical to the amino acid sequence of SEQ ID NO:41 and/or a light chain amino acid sequence at least about 90% identical to the amino acid sequence of SEQ ID NO:42.
  • the CTLA-4 binding protein comprises a heavy chain sequence of SEQ ID NO:41 and a light chain sequence of SEQ ID NO:42.
  • an CTLA-4 binding protein is type IgG1, IgG2, IgG3 or IgG4 constant region.
  • the CTLA-4 binding protein is type IgG1.
  • a method of treating cancer in a human in need thereof comprising administering to the human an agonist ICOS binding protein or antigen binding portion thereof at a dose of about 0.08 mg to about 240 mg and administering to the human a CTLA-4 binding protein or antigen binding portion thereof, wherein the CTLA-4 binding protein or antigen binding portion thereof comprises one or more of CDRH1 as set out in SEQ ID NO:33; CDRH2 as set out in SEQ ID NO:34; CDRH3 as set out in SEQ ID NO:35; CDRL1 as set out in SEQ ID NO:36; CDRL2 as set out in SEQ ID NO:37 and/or CDRL3 as set out in SEQ ID NO: 38.
  • the CTLA-4 binding protein is ipilimumab. It will be understood that aspects and embodiments of the invention pertaining to ipilimumab also apply to the CTLA-4 binding protein or antigen binding portion thereof disclosed herein.
  • Methods of Treatment The therapeutic agents described herein may also be used in methods of treatment. It will be appreciated by those skilled in the art that references herein to treatment refer to the treatment of established conditions. However, compositions of the invention may, depending on the condition, also be useful in the prevention of certain diseases.
  • the therapeutic agents described herein can be used in an effective amount for therapeutic, prophylactic or preventative treatment. A therapeutically effective amount of the therapeutic agents described herein is an amount effective to ameliorate or reduce one or more symptoms of, or to prevent or cure, the disease.
  • a method of treating cancer in a human in need thereof comprising administering to the human an agonist ICOS binding protein or antigen binding portion thereof at a dose of about 0.08 mg to about 240 mg and administering to the human ipilimumab.
  • a combination comprising an agonist ICOS binding protein or antigen binding portion thereof and ipilimumab for use in treating cancer, wherein the ICOS binding protein or antigen binding portion thereof is to be administered at a dose of about 0.08 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 administered at a dose of about 0.08 mg to about 240 mg and is administered with ipilimumab.
  • use of an agonist ICOS binding protein or antigen binding portion thereof in the manufacture of a medicament for treating cancer wherein the agonist ICOS binding protein or antigen binding portion thereof is administered at a dose of about 0.08 mg to about 240 mg and is administered with ipilimumab.
  • a composition comprising an agonist ICOS binding protein or antigen binding portion thereof at about 0.08 mg to about 240 mg and ipilimumab.
  • a pharmaceutical kit comprising about 0.08 mg to about 1000 mg of an ICOS binding protein or antigen binding portion thereof and ipilimumab.
  • Routes of administration and dosages The doses provided in the present application are suitable for mammals, in particular a human. It is to be understood that where agonist ICOS binding protein is used herein, the antigen binding portion thereof is also implied.
  • a therapeutically effective dose of the agonist ICOS binding protein is a dose of about 0.01 - 1000 mg (e.g.
  • the agonist ICOS binding protein or antigen binding portion thereof is administered at a dose of about 0.08 mg to about 240 mg. In one embodiment, the agonist ICOS binding protein is administered at a dose of 0.08 mg, 0.24 mg, 0.8 mg, 2.4 mg, 8 mg, 24 mg, 48 mg, 80 mg, 160 mg or 240 mg in particular 24 mg, 48 mg, 80 mg or 160 mg. It is to be understood that where mg/kg is used, this is mg/kg of body weight. In some embodiments, a therapeutically effective dose of the agonist ICOS binding protein is a dose of about 0.001 mg/kg to 10 mg/kg. In some embodiments, a therapeutically effective dose is about 0.001 mg/kg.
  • a therapeutically effictive dose is about 0.003 mg/kg. In some embodiments, a therapeutically effective dose is about 0.01 mg/kg. In some embodiments, a therapeutically effective dose is about 0.03 mg/kg. In some embodiments, a therapeutically effective dose is about 0.1 mg/kg. In some embodiments, a therapeutically effective dose is about 0.3 mg/kg. In some embodiments, a therapeutically effective dose is about 0.6 mg/kg. In some embodiments, a therapeutically effective dose is about 1 mg/kg. In some embodiments, a therepeutically effective dose is about 2 mg/kg. In some embodiments, a therapeutically effective dose is about 3 mg/kg.
  • a therapeutically effective dose is about 4 mg/kg; about 5 mg/kg; about 6 mg/kg; about 7 mg/kg; about 8 mg/kg; about 9 mg/kg or about 10 mg/kg.
  • the dose of the agonist ICOS binding protein is between about 0.001 mg/kg to about 3.0 mg/kg.
  • the dose of the agonist ICOS binding protein is about 0.001 mg/kg, about 0.003 mg/kg, about 0.01 mg/kg, about 0.03 mg/kg, about 0.1 mg/kg, about 0.3 mg/kg, about 1.0 mg/kg, about 3.0 mg/kg, or about 10 mg/kg.
  • the dose of agonist ICOS binding protein is about 0.3 mg/kg.
  • the dose of the agonist ICOS binding protein is at least 3.0 mg/kg. In one embodiment, the dose of the agonist ICOS binding protein is in the range of about 0.001 mg/kg to about 10 mg/kg. In one embodiment, the dose of the agonist ICOS protein is about 0.1 mg/kg to about 3 mg/kg. In one embodiment, the dose of the ICOS binding protein is about 0.1 mg/kg to about 1.0 mg/kg. In one embodiment, the dose of the agonist ICOS binding protein is about 0.1 mg/kg. In one embodiment, the dose of the ICOS binding protein is at least 0.1 mg/kg. In another embodiment, the dose of the agonist ICOS binding protein is about 0.3 mg/kg.
  • the dose of the agonist ICOS binding protein is about 1 mg/kg. In one embodiment, the dose of the agonist ICOS binding protein is about 3 mg/kg. In one embodiment, a fixed dose of agonist ICOS binding protein may be administered, assuming a typical median weight of 80 kg. In one embodiment, the dose of agonist ICOS binding protein is increased during the treatment regimen.
  • an initial dose of about 0.001 mg/kg, about 0.003 mg/kg, about 0.01 mg/kg, about 0.03 mg/kg, about 0.1 mg/kg, about 0.3 mg/kg, about 1.0 mg/kg is increased to about 0.003 mg/kg, about 0.01 mg/kg, about 0.03 mg/kg, about 0.1 mg/kg, about 0.3 mg/kg, about 1.0 mg/kg, about 3.0 mg/kg or at least 3.0 mg/kg.
  • an initial dose of 0.1 mg/kg is increased to 1 mg/kg.
  • an initial dose of 0.3 mg/kg is increased to 1 mg/kg.
  • the initial dose of 0.6 mg/kg is increased to 2 mg/kg.
  • the agonist ICOS binding protein is administered at 0.1 mg/kg x 3 doses then 1 mg/kg. In one embodiment, the agonist ICOS binding protein is administered at about 0.001 mg/kg, about 0.003 mg/kg, about 0.01 mg/kg, about 0.03 mg/kg, about 0.1 mg/kg, about 0.3 mg/kg, about 1.0 mg/kg, or about 3.0 mg/kg then increased to about 0.01 mg/kg, about 0.03 mg/kg, about 0.1 mg/kg, about 0.3 mg/kg, about 1.0 mg/kg, about 3.0 mg/kg or about 10 mg/kg. In one embodiment, ipilimumab is administered at a dose of about 0.3 mg/kg to about 15 mg/kg.
  • ipilimumab is administered at a dose of about 0.3 mg/kg to about 10 mg/kg. In one embodiment, ipilimumab is administered at a dose of about 1 mg/kg to about 10 mg/kg. In one embodiment, ipilimumab is administered at a dose of 3 mg/kg to about 10 mg/kg. In one embodiment, ipilimumab is administered at a dose of about 6 mg/kg to 10 mg/kg. In one embodiment, ipilimumab is administered at a dose of about 0.3 mg/kg to about 6 mg/kg. In one embodiment, ipilimumab is administered at a dose of about 1 mg/kg to about 6 mg/kg.
  • ipilimumab is administered at a dose of 3 mg/kg to about 6 mg/kg. In one embodiment, ipilimumab is administered at a dose of about 0.3 mg/kg to about 3 mg/kg. In one embodiment, ipilimumab is administered at a dose of about 1 mg/kg to about 3 mg/kg. In one embodiment, ipilimumab is administered at a dose of about 0.3 mg/kg to about 1 mg/kg.
  • ipilimumab is administed at a dose of about 0.3 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg or about 10 mg/kg.
  • ipilimumab is administered at a dose of about 1 mg/kg.
  • ipilimumab is administered at a dose of about 3 mg/kg.
  • ipilimumab is administered at a dose of about 10 mg/kg.
  • ipilimumab is administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 weeks. In one embodiment, ipilimumab is administered once every 6 weeks. In one embodiment, ipilimumab is administered once every 12 weeks. In one embodiment, ipilimumab is administered for up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 cycles. In one embodiment, ipilimumab is administered for up to 3 years, until disease progression or unacceptable toxicity. In one embodiment, ipilimumab is administered for a total of 4 doses. In one embodiment, ipilimumab is administered once every 3 weeks for a total of 4 doses.
  • ipilimumab is administered once every three weeks for 4 doses and then every 12 weeks. In one embodiment, ipilimumab is administered once every three weeks for 4 doses and then every 12 weeks for up to three years, disease progression or unacceptable toxicity. In one embodiment, ipilimumab is administered at a dose of about 1 mg/kg once every three weeks for a total of 4 cycles. In one embodiment, ipilimumab is administered at a dose of about 3 mg/kg once every three weeks for a total of 4 cycles. In one embodiment, ipilimumab is administered once every three weeks.
  • ipilimumab is administered once every three weeks and then once every six weeks. In one embodiment, ipilimumab is administered once every three weeks and then once every six weeks if there is toxicity. In one embodiment, ipilimumab is administered at a dose of about 3 mg/kg once every 3 weeks and then at a dose of about 1 mg/kg once every three weeks. In one embodiment, ipilimumab is administered at a dose of about 3 mg/kg once every 3 weeks and then at a dose of about 1 mg/kg once every three weeks if there is toxicity.
  • ipilimumab is administered at a dose of about 1 mg/kg once every three weeks and then 1 mg/kg once every six weeks. In one embodiment, ipilimumab is administered at a dose of about 1 mg/kg once every three weeks and then 1 mg/kg once every six weeks if there is toxicity. In one embodiment, ipilimumab is administered at a dose of about 3 mg/kg once every three weeks and then 3 mg/kg once every six weeks. In one embodiment, ipilimumab is administered at a dose of about 3 mg/kg once every three weeks and then 3 mg/kg once every six weeks if there is toxicity.
  • the ICOS binding protein or antigen binding portion thereof and ipilimumab are administered for up to 2 years, disease progression or unacceptable toxicity. In one embodiment, the ICOS binding protein or antigen binding portion thereof and ipilimumab are administered once every 3 weeks. In one embodiment, the ICOS binding protein or antigen binding portion thereof is administered once every 3 weeks and ipilimumab is administered once every 3 weeks. In one embodiment, the agonist ICOS binding protein or antigen binding portion thereof and ipilimumab are administered on the same day every 3 weeks.
  • the agonist ICOS binding protein or antigen binding portion thereof and ipilimumab are administered on the same day every 3 weeks for up to 4 doses starting on day 1.
  • the ICOS binding protein or antigen binding portion thereof is administered once every 3 weeks and ipilimumab is administered once every 3 weeks.
  • the frequency of the administration of ipilimumab may be reduced from once every three weeks to once every six weeks.
  • the ICOS binding protein or antigen binding portion thereof and ipilimumab are administered once every once every 3 weeks, followed by administration of the ICOS binding protein or antigen binding portion thereof once every three weeks and ipilimumab once every six weeks.
  • the ICOS binding protein or antigen binding portion thereof and ipilimumab are administered once every once every 3 weeks, and then once every six weeks. In one embodiment, the ICOS binding protein or antigen binding portion thereof is administered every 3 weeks and ipilimumab is administered every 3 weeks for 4 cycles, followed by further administration of the ICOS binding protein or antigen binding portion thereof only. In one embodiment, the ICOS binding protein or antigen binding portion thereof is administered every 3 weeks and ipilimumab is administered every 3 weeks for 4 cycles, followed by further administration of the ICOS binding protein or antigen binding portion thereof once every three weeks.
  • the ICOS binding protein or antigen binding portion thereof is administered every 3 weeks and ipilimumab is administered every 3 weeks for 4 cycles, followed by further administration of the ICOS binding protein or antigen binding portion thereof once every 6 or 12 weeks.
  • ipilimumab is administered as an IV infusion over 30, 60 or 90 minutes.
  • ipilimumab is administered as an IV infusion over 30 minutes.
  • ipilimumab is administered as an IV infusion over 60 minutes.
  • ipilimumab is administered as an IV infusion over 90 minutes.
  • ipilimumab is administered as an IV infusion over 90 minutes at a dose of about 1 mg/kg, about 3 mg/kg or 10 mg/kg. In one embodiment, ipilimumab is administered as an IV infusion over 60 minutes at a dose of about 1 mg/kg, about 3 mg/kg or 10 mg/kg. In one embodiment, ipilimumab is administered as an IV infusion over 30 minutes at a dose of about 1 mg/kg, about 3 mg/kg or 10 mg/kg. In one embodiment, ipilimumab is administered as an IV infusion over 30 minutes at a dose of about 3 mg/kg.
  • ipilimumab is administered as an IV infusion over 90 minutes at a dose of about 3 mg/kg.
  • the ICOS binding protein or antigen binding portion thereof is administered as a 30, 60 or 90 minute IV infusion. In some embodiments, the ICOS binding protein or antigen binding portion thereof is administered at as an IV infusion over 30 minutes. In some embodiments, the ICOS binding protein or antigen binding portion thereof is administered at as an IV infusion over 60 minutes. In some embodiments, the ICOS binding protein or antigen binding portion thereof is administered at as an IV infusion over 90 minutes. In one embodiment, ipilimumab is administered prior to administration of the ICOS binding protein or antigen binding portion thereof.
  • the ICOS binding protein or antigen binding portion thereof is administered prior to administration of ipilimumab. In one embodiment, the ICOS binding protein or antigen binding portion thereof is administered first as an IV infusion over 30, 60 or 90 minutes and ipilimumab is administered as an IV infusion over 30 minutes beginning at least 30 minutes and no more than 2 hours following the end of the infusion of the ICOS binding protein or antigen binding portion thereof.
  • the ICOS binding protein or antigen binding portion thereof is administered first as an IV infusion over 30, 60 or 90 minutes and ipilimumab is administered as an IV infusion over 30 minutes beginning at least 1 hour and no more than 2 hours following the end of the infusion of the ICOS binding protein or antigen binding portion thereof.
  • ipilimumab is administered first as an IV infusion over 30, 60 or 90 minutes and the ICOS binding protein or antigen binding portion thereof is administered as an IV infusion over 30 minutes beginning at least 30 minutes and no more than 2 hours following the end of the ipilimumab infusion.
  • ipilimumab is administered first as an IV infusion over 30, 60 or 90 minutes and the ICOS binding protein or antigen binding portion thereof is administered as an IV infusion over 30 minutes beginning at least 1 hour and no more than 2 hours following the end of the ipilimumab infusion. In some embodiments, ipilimumab is administered prior to administration of the agonist ICOS binding protein or antigen binding portion thereof. In some embodiments, the agonist ICOS binding protein or antigen binding portion thereof is administered within 30 minutes and no longer than 3 hours following the end of administration of ipilimumab.
  • the agonist ICOS binding protein or antigen binding portion thereof is administered within 1 hour and no longer than 2 hours following the end of administration of ipilimumab. In some embodiments, the agonist ICOS binding protein or antigen binding portion thereof is administered prior to ipilimumab. In some embodiments, ipilimumab is administered within at least 30 minutes and no longer than one hour following administration of the agonist ICOS binding protein or antigen binding portion thereof. In one embodiment, the ICOS binding protein or antigen binding portion thereof is administered at a dose of about 8 mg to about 80 mg and ipilimumab is administered at a dose of about 1 mg/kg to about 10 mg/kg.
  • the ICOS binding protein or antigen binding portion thereof is administered at a dose of about 24 mg or about 80 mg and ipilimumab is administered at a dose of about 1 mg/kg, about 3 mg/kg or about 10 mg/kg. In one embodiment, the ICOS binding protein or antigen binding portion thereof is administered at a dose of about 8 mg and ipilimumab is administered at about 1 mg/kg. In one embodiment, the ICOS binding protein or antigen binding portion thereof is administered at a dose of about 8 mg and ipilimumab is administered at about 3 mg/kg.
  • the ICOS binding protein or antigen binding portion thereof is administered at a dose of about 24 mg and ipilimumab is administered at about 1 mg/kg. In one embodiment, the ICOS binding protein or antigen binding portion thereof is administered at a dose of about 24 mg and ipilimumab is administered at about 3 mg/kg. In one embodiment, the ICOS binding protein or antigen binding portion thereof is administered at a dose of about 80 mg and ipilimumab is administered at about 1 mg/kg. In one embodiment, the ICOS binding protein or antigen binding portion thereof is administered at a dose of about 80 mg and the ipilimumab is administered at about 3 mg/kg.
  • a method of treating cancer in a human in need thereof comprising administering to the human an agonist ICOS binding protein or antigen binding portion thereof at a dose of about 0.08 mg to about 240 mg and administering to the human ipilimumab at a dose of about 0.3 mg/kg to about 10 mg/kg, 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.
  • a combination of an agonist ICOS binding protein or antigen binding portion thereof and ipilimumab for use in treating cancer wherein the ICOS binding protein or antigen binding portion thereof is administered at a dose of about 0.08 mg to about 240 mg and ipilimumab at a dose of about 0.3 mg/kg to about 10 mg/kg, 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.
  • 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 administered at a dose of about 0.08 mg to about 240 mg and is administered concurrently and/or sequentially with ipilimumab at a dose of about 0.3 mg/kg to about 10 mg/kg, wherein the agonist 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 agonist ICOS binding protein specifically binds to human ICOS.
  • an agonist ICOS binding protein or antigen binding portion thereof in the manufacture of a medicament for treating cancer, wherein the agonist ICOS binding protein or antigen binding portion thereof is to be administered at a dose of about 0.08 mg to about 240 mg and is administered concurrently and/or sequentially with ipilimumab at a dose of about 0.3 mg/kg to about 10 mg/kg, wherein the ICOS binding protein comprises a V H 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.
  • a pharmaceutical kit comprising about 0.08 mg to about 240 mg of an agonist ICOS binding protein or antigen binding portion thereof and ipilimumab at a dose of about 0.3 mg/kg to about 10 mg/kg, 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.
  • the therapeutic agents disclosed herein may be administered either in separate or combined form (e.g. as pharmaceutical formulations) by any convenient route.
  • suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intraveneous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that the therapeutic agents may be formulated together or in separate pharmaceutical compositions. In one embodiment, the therapeutic agent(s) is administered intravenously. In a further embodiment, the therapeutic agent(s) is administered by intravenous infusion. In another embodiment, the therapeutic agent(s) administered intratumorally.
  • the therapeutic agent(s) is administered orally. In another embodiment, the therapeutic agent(s) is administered systemically, e.g. intravenously, and one or more other therapeutic agents of the invention are administered intratumorally. In another embodiment, all of the therapeutic agents are administered systemically, e.g. intravenously. In an alternative embodiment, all of the therapeutic agents are administered intratumorally. In any of the embodiments, e.g. in this paragraph, the therapeutic agents of the invention may be administered as one or more pharmaceutical compositions. In one embodiment, the agonist ICOS binding protein or antigen binding portion thereof is administered via intravenous (IV) infusion. In one embodiment, the agonist ICOS binding protein or antigen binding portion thereof is administered via intravenous (IV) infusion over 30 minutes.
  • ipilimumab is administered via IV infusion. In one embodiment, ipilimumab is administered via intravenous (IV) infusion over 30, 60 or 90 minutes. In one embodiment, the agonist ICOS binding protein or antigen binding portion thereof and ipilimumab are administered via IV infusion. In one embodiment, the agonist ICOS binding protein or antigen binding portion thereof is administered concurrently or sequentially with ipilimumab. In another embodiment, the agonist ICOS binding protein or antigen binding portion thereof is administered concurrently with ipilimumab. In another embodiment, the agonist ICOS binding protein or antigen binding portion thereof is administered sequentially with ipilimumab.
  • the therapeutic agent(s) are 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. In one embodiment, the therapeutic agent(s) are administered once every 1 to 12 weeks.
  • the therapeutic agent(s) are administered once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, once every 10 weeks, once every 11 weeks or once every 12 weeks. In one embodiment, the therapeutic agent(s) are administered once every 3 weeks. In one embodiment, the therapeutic agent(s) are administered once every 6 weeks. In one embodiment the agonist ICOS binding protein or antigen binding fragment thereof is administered once every 3 weeks. In one embodiment, ipilimumab is administered once every three weeks.
  • the agonist ICOS binding protein or antigen binding portion thereof and ipilimumab are administered once every 3 weeks for4 doses and the agonist ICOS binding protein or antigen binding portion thereof once every 3 weeks thereafter.
  • the combination is administered once every 3 weeks for 2-6 dosing cycles (e.g. the first 3, 4, or 5 dosing cycles, in particular, the first 4 dosing cycles).
  • the therapeutic agent(s) are administered for up to 2 years or unacceptable toxcity. In one embodiment, the therapeutic agent(s) are administered every three weeks up to 35 cycles or unacceptable toxicity.
  • the effective daily dose of a (therapeutic) combination may be administered as two, three, four, five, six or more doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the present disclosure provides methods of treating cancer comprising administering to a patient in need of treatment one or both of the therapeutic agents at a first dose at a first interval for a first period; and administering to the patient one or both of the therapeutic agents at a second dose at a second interval for a second period. There may be a rest period between the first and second periods in which one or both of the binding proteins (i.e.
  • the agonist ICOS binding portein or antigen binding portion thereof and ipilimumab or CTLA-4 binding protein or antigen binding portion thereof) in the combination are not administered to the patient.
  • the rest period is between 1 and 30 days.
  • the rest period is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 days.
  • the rest period is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks or 15 weeks.
  • the first dose and second dose are the same.
  • the first interval and second interval are the same. In some embodiments, the first interval and the second interval are once every three weeks. In some embodiments, the first interval and the second interval are once every six weeks. In some embodiments, the first interval and the second interval are different. In some embodiments, the first interval is once every three weeks and the second interval is once every six weeks. In some embodiments, the first interval is once every three weeks and the second interval is once every twelve weeks. In some embodiments, the first interval and the second interval are different. In some embodiments, the first interval is once every three weeks and the second interval is once every six weeks. In some embodiments, the therapeutic agent is administered at a first dose of 24 mg once every three weeks for the first period of 2-6 dosing cycles (e.g.
  • a clinical benefit is stable disease ("SD"), a partial response (“PR") and/or a complete response (“CR”).
  • a clinical benefit is stable disease ("SD”).
  • a clinical benefit is a partial response ("PR”).
  • a clinical benefit is a complete response ("CR”).
  • PR or CR is determined in accordance with Response Evaluation Criteria in Solid Tumors (RECIST).
  • the combination is administered for a longer period to maintain clinical benefit.
  • a pharmaceutical kit comprising an ICOS binding protein or an antigen binding portion thereof and ipilimumab.
  • the pharmaceutical kit comprises about 0.08 mg to about 1000 mg of an agonist ICOS binding protein or antigen binding portion thereof and about 20 mg to about 1000 mg of ipilimumab.
  • the pharmaceutical kit comprises about 0.08 mg to about 240 mg of the agonist ICOS binding protein or antigen binding portion thereof and ipilimumab.
  • the pharmaceutical kit comprises a further immunomodulatory agent.
  • the further immunomodulatory agent is a PD-1 binding protein or an antigen binding portion thereof, a PD-L1 binding protein or an antigen binding portion thereof.
  • the pharmaceutical kit comprises the agonist ICOS binding protein or antigen binding portion thereof at a concentration of 10 mg/ml.
  • the pharmaceutical kit comprises ipilimumab at a concentration of 5 mg/ml.
  • the pharmaceutical kit comprises the ICOS binding protein or an antigen binding portion thereof at about 10 mg/ml and ipilimumab at about 5 mg/ml.
  • the pharmaceutical kit comprises the PD-1 binding protein at a concentration of about 20 mg/mL to about 125 mg/mL. In a further embodiment, the pharmaceutical kit comprises the PD-1 binding protein at a concentration of 20 mg/mL to 50 mg/mL. In one embodiment, the PD-1 binding protein is at a concentration of 20 mg/mL. In another embodiment, the PD-1 binding protein is at a concentration of 50 mg/mL. In some embodiments, the method, agonist ICOS binding protein, combination, use, or kit of the invention further comprises administration of a chemotherapeutic agent. Chemotherapeutic agents, also referred to as anti-neoplastic agents, are used to directly or indirectly inhibit the proliferation of rapidly growing cells, typically in the context of malignancy.
  • anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; non-receptor tyrosine kinase angiogenesis inhibitors; proapoptotic agents
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti- microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • Diterpenoids which are derived from natural sources, are phase specific anti -cancer agents that operate at the G2/M phases of the cell cycle. It is believed that the diterpenoids stabilize the ⁇ - tubulin subunit of the microtubules, by binding with this protein.
  • Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following.
  • diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • the chemotherapeutic agent is paclitaxel or docetaxel.
  • Paclitaxel 5 ⁇ ,20-epoxy-1,2 ⁇ ,4,7 ⁇ ,10 ⁇ ,13 ⁇ -hexa-hydroxytax-11-en-9-one 4,10-diacetate 2- benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL ⁇ . It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc., 93:2325.
  • Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann. lntem, Med., 111:273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.) It is a potential candidate for treatment of neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin.
  • the chemotherapeutic agent is paclitaxel. In another embodiment, paclitaxel is administered once every three weeks. In one embodiment, paclitaxel is administered by intravenous (IV) infusion. In one embodiment, paclitaxel is administered at a dose of 135 mg/m 2 or 175 mg/m 2 . In one embodiment, paclitaxel is administered at a dose of 175 mg/m 2 every three weeks. In one embodiment, paclitaxel is administered at a dose of 175 mg/m 2 over 3 hours every three weeks. In one embodiment, paclitaxel is administered at a dose of 135 mg/m 2 once every three weeks.
  • IV intravenous
  • paclitaxel is administered at a dose of 135 mg/m 2 over 24 hours, once every three weeks.
  • Docetaxel is indicated for the treatment of breast cancer.
  • Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree.
  • the dose limiting toxicity of docetaxel is neutropenia.
  • the chemotherapeutic agent is docetaxel.
  • docetaxel is administered by IV infusion.
  • docetaxel is administered at a dose of 75 mg/m 2 .
  • docetaxel is administered at a dose of 75 mg/m 2 over 1 hour.
  • docetaxel is administered once every three weeks.
  • docetaxel is administered at a does of 60 to 100 mg/m 2 via IV over 1 hour every three weeks.
  • Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine. Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN ⁇ as an injectable solution.
  • vincristine is administered at a dose of 1.4 mg/m 2 . In one embodiment, vincristine is administered once a week.
  • Vinorelbine 3’,4’-didehydro-4’-deoxy-C’-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (1:2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE ⁇ ), is a semisynthetic vinca alkaloID Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
  • platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA.
  • the platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor.
  • Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
  • the chemotherapeutic agent is a platinum-based chemotherapy doublet.
  • the platinum-based chemotherapy doublet is 5-FU/carboplatin.
  • the platinum-based chemotherapy doublet is 5-FU/cisplatin.
  • the chemotherapeutic agent is selected from one or more of the following: pemetrexed, gemcitabine, fluorouracil (5-FU) paclitaxel, docetaxel, cisplatin or carboplatin.
  • the chemotherapeutic agent is pemetrexed/carboplatin or pemetrexed/cisplatin doublet.
  • the chemotherapeutic agent is paclitaxel/carboplatin or paclitaxel/cisplatin doublet.
  • the chemotherapeutic agent is gemcitabine/carboplatin or gemcitabine cisplatin doublet.
  • the chemotherapeutic agent is selected from one or more of the following: paclitaxel, docetaxel, or carboplatin.
  • Cisplatin, cis-diamminedichloroplatinum is commercially available as PLATINOL ⁇ as an injectable solution.
  • Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
  • the primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
  • the chemotherapeutic agent is cisplatin.
  • cisplatin is administered at a dose of 100 mg/m 2 once every four weeks.
  • cisplatin is administered at a dose of about 75 mg/m 2 to about 100 mg/m 2 once every four weeks. In one embodiment, cisplatin is administered at a dose of about 50 mg/m 2 to about 70 mg/m 2 once every three to four weeks.
  • Carboplatin, platinum, diammine [1,1-cyclobutane-dicarboxylate(2-)-O,O’] is commercially available as PARAPLATIN ⁇ as an injectable solution. Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
  • the chemotherapeutic agent is carboplatin.
  • carboplatin is administered at a dose of about 360 mg/m 2 every four weeks. In one embodiment, carboplatin is administered at a dose of about 300 mg/m 2 every four weeks.
  • Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death.
  • alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
  • nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil
  • alkyl sulfonates such as busulfan
  • nitrosoureas such as carmustine
  • triazenes such as dacarbazine.
  • Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2- oxide monohydrate is commercially available as an injectable solution or tablets as CYTOXAN ⁇ .
  • Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
  • the chemotherapeutic agent is cisplatin or carboplatin.
  • the chemotherapeutic agent is selected from one or more of the following: paclitaxel, docetaxel, cisplatin, carboplatin, or cyclophosphamide.
  • the chemotherapeutic agent is cyclophosphamide.
  • the chemotherapeutic agent is docetaxel, pemetrexed, gemcitabine, carboplatin, cisplatin, paclitaxel, fluorouracil or a combination thereof.
  • the chemotherapeutic agent is a platinum-based chemotherapy doublet.
  • the chemotherapeutic agent is fluorouracil and carboplatin (5-FU/carboplatin).
  • the chemotherapeutic agent is fluorouracil and cisplatin (5-FU/cisplatin).
  • a description of the chemotherapy and administration is provided in Table 10.
  • cyclophosphamide is administered at a dose of about 40 mg/m 2 to about 50 mg/m 2 every two to five days.
  • cyclophosphamide is administered at a dose of about 10 mg/kg to about 15 mg/kg every 7 to 10 days or 5 mg/kg 2 times a week. In one embodiment, cyclophosphamide is administered via IV infusion.
  • Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN ⁇ . Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
  • melphalan is administered at a dose of 2 mg or 6 mg, once daily. In one embodiment, melphalan is administered at a dose of 0.2 mg/kg daily.
  • Chlorambucil 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN ⁇ tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin’s disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.
  • chlorambucil is administered at a dose of 0.1 to 0.2 mg/kg daily or 4 to 10 mg daily.
  • Busulfan 1,4-butanediol dimethanesulfonate, is commercially available as MYLERAN ⁇ TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan. In one embodiment, busulfan is administered at a dose of 1.8mg/m 2 daily.
  • Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea is commercially available as single vials of lyophilized material as BiCNU ⁇ .
  • Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin’s disease, and non- Hodgkin’s lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
  • carmustine is administered at 150 to 200 mg/m 2 IV every 6 weeks.
  • dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome ⁇ .
  • dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin’s Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine. In one embodiment, dacarbazine is administered at 150 mg/m 2 IV once a day or 375 mg/m 2 IV every 15 days.
  • Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids leading to cell death.
  • antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins.
  • Dactinomycin also know as Actinomycin D, is commercially available in injectable form as COSMEGEN ⁇ . Dactinomycin is indicated for the treatment of Wilm’s tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
  • Daunorubicin (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy- ⁇ -L-lyxo-hexopyranosyl)oxy]- 7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME ⁇ or as an injectable as CERUBIDINE ⁇ . Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi’s sarcoma.
  • Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.
  • Bleomycin a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE ⁇ .
  • Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
  • Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
  • Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows.
  • Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Etoposide, 4’-demethyl-epipodophyllotoxin 9[4,6-0-(R )-ethylidene- ⁇ -D-glucopyranoside] is commercially available as an injectable solution or capsules as VePESID ⁇ and is commonly known as VP-16.
  • Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
  • Teniposide, 4’-demethyl-epipodophyllotoxin 9[4,6-0-(R )-thenylidene- ⁇ -D-glucopyranoside], is commercially available as an injectable solution as VUMON ⁇ and is commonly known as VM-26.
  • Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows.
  • antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine. 5-fluorouracil, 5-fluoro-2,4- (1H,3H) pyrimidinedione, is commercially available as fluorouracil.
  • 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
  • 5-fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil.
  • Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
  • fluorouracil is administered 1000mg/m 2 /day on day 1 through day 4 of every 21 day cycle (Q3W).
  • Cytarabine 4-amino-1- ⁇ -D-arabinofuranosyl-2 (1H)-pyrimidinone, is commercially available as CYTOSAR-U ⁇ and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2’,2’-difluorodeoxycytidine (gemcitabine).
  • Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
  • Mercaptopurine 1,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL ⁇ .
  • Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses.
  • a useful mercaptopurine analog is azathioprine.
  • Thioguanine 2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID ⁇ .
  • Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting.
  • Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.
  • Gemcitabine 2’-deoxy-2’, 2’-difluorocytidine monohydrochloride ( ⁇ -isomer), is commercially available as GEMZAR ⁇ .
  • Gemcitabine exhibits cell phase specificity at S-phase and by blocking progression of cells through the G1/S boundary.
  • Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
  • Methotrexate N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L-glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate.
  • Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin’s lymphoma, and carcinomas of the breast, head, neck, ovary and bladder.
  • Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.
  • Camptothecins including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity.
  • camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,11- ethylenedioxy-20-camptothecin described below.
  • Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-1H- pyrano[3’,4’,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione hydrochloride is commercially available as the injectable solution CAMPTOSAR ⁇ .
  • Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I – DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCl are myelosuppression, including neutropenia, and GI effects, including diarrhea.
  • Topotecan HCl (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H- pyrano[3’,4’,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN ⁇ .
  • Topotecan is a derivative of camptothecin which binds to the topoisomerase I – DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer.
  • mTOR inhibitors include but are not limited to rapamycin (FK506) and rapalogs, RAD001 or everolimus (Afinitor), CCI-779 or temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687 and Pp121.
  • Bexarotene is sold as Targretin® and is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs).
  • the chemical name is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8- pentamethyl-2-naphthalenyl) ethenyl] benzoic acID Bexarotene is used to treat cutaneous T-cell lymphoma CTCL, a type of skin cancer) in people whose disease could not be treated successfully with at least one other medication.
  • Sorafenib marketed as Nexavar® is in a class of medications called multikinase inhibitors.
  • Its chemical name is 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl- pyridine-2-carboxamide.
  • Sorafenib is used to treat advanced renal cell carcinoma (a type of cancer that begins in the kidneys). Sorafenib is also used to treat unresectable hepatocellular carcinoma (a type of liver cancer that cannot be treated with surgery).
  • erbB inhibitors include lapatinib, erlotinib, and gefitinib.
  • Lapatinib N-(3-chloro- 4- ⁇ [(3-fluorophenyl)methyl]oxy ⁇ phenyl)-6-[5-( ⁇ [2-(methylsulfonyl)ethyl]amino ⁇ methyl)-2-furanyl]-4- quinazolinamine (represented by formula II, as illustrated), is a potent, oral, small-molecule, dual inhibitor of erbB-1 and erbB-2 (EGFR and HER2) tyrosine kinases that is approved in combination with capecitabine for the treatment of HER2-positive metastatic breast cancer.
  • erbB-1 and erbB-2 EGFR and HER2
  • the free base, HCl salts, and ditosylate salts of the compound of formula (II) may be prepared according to the procedures disclosed in WO 99/35146, published July 15, 1999; and WO 02/02552 published January 10, 2002.
  • Erlotinib, N-(3-ethynylphenyl)-6,7-bis ⁇ [2-(methyloxy)ethyl]oxy ⁇ -4-quinazolinamine Commercially available under the tradename Tarceva
  • the free base and HCl salt of erlotinib may be prepared, for example, according to U.S. 5,747,498, Example 20.
  • Gefitinib 4-quinazolinamine,N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4- morpholin)propoxy] is represented by formula IV, as illustrated:
  • Gefitinib which is commercially available under the trade name IRESSA ⁇ (Astra-Zenenca) is an erbB-1 inhibitor that is indicated as monotherapy for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of both platinum-based and docetaxel chemotherapies.
  • the free base, HCl salts, and diHCl salts of gefitinib may be prepared according to the procedures of International Patent Application No.
  • camptothecin derivative of formula A following, currently under development, including the racemic mixture (R,S) form as well as the R and S enantiomers: known by the chemical name “7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy- 20(R,S)-camptothecin (racemic mixture) or “7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy- 20(R)-camptothecin (R enantiomer) or “7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy- 20(S)-camptothecin (S enantiomer).
  • Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation.
  • Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3domain blockers, serine/threonine kinases, phosphotidyl inositol-3 kinases, myo-inositol signaling, and Ras oncogenes.
  • Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
  • Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods.
  • Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor –I (IGFI) receptor, macrophage colony stimulating factor Cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene.
  • EGFr epidermal growth factor receptor
  • PDGFr platelet derived growth factor receptor
  • erbB2 erbB4
  • VEGFr vascular endothelial growth factor receptor
  • TIE-2 vascular endothelial growth factor receptor
  • TIE-2 insulin growth factor
  • inhibitors of growth receptors include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.
  • Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C., Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, F. J. et al, “Growth factor receptors as targets”, New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
  • Non-receptor tyrosine kinases which are not growth factor receptor kinases are termed non-receptor tyrosine kinases.
  • Non-receptor tyrosine kinases useful in the present invention include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl.
  • Such non-receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S.
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck, Grb2) and Ras-GAP.
  • SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.
  • Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).
  • IkB kinase family IKKa, IKKb
  • PKB family kinases AKT kinase family members
  • TGF beta receptor kinases TGF beta receptor kinases.
  • Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60.1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys.27:41-64; Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S.
  • Inhibitors of Phosphotidyl inositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku are also useful in the present invention.
  • Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H.
  • Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues.
  • signal inhibitors are described in Powis, G., and Kozikowski A., (1994 New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
  • Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene.
  • inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy.
  • Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents.
  • Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 – 102; and Bennett, C.F.
  • antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors.
  • This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases.
  • Imclone C225 EGFR specific antibody see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat.
  • Non-receptor kinase angiogenesis inhibitors may also find use in the present invention.
  • Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases).
  • Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression.
  • the combination of an erbB2/EGFR inhibitor with an inhibitor of angiogenesis makes sense.
  • non-receptor tyrosine kinase inhibitors may be used in combination with the EGFR/erbB2 inhibitors of the present invention.
  • anti-VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alphav beta3) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed erb family inhibitors.
  • VEGFR the receptor tyrosine kinase
  • small molecule inhibitors of integrin alphav beta3
  • endostatin and angiostatin non-RTK
  • Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of formula (I).
  • immunologic strategies to generate an immune response against erbB2 or EGFR. These strategies are generally in the realm of tumor vaccinations.
  • the efficacy of immunologic approaches may be greatly enhanced through combined inhibition of erbB2/EGFR signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.
  • Agents used in proapoptotic regimens may also be used in the combination of the present invention.
  • Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance.
  • EGF epidermal growth factor
  • the chemotherapeutic agent(s) is one or a combination of chemotherapeutic agents selected from docetaxel, pemetrexed, paclitaxel, gemcitabine, 5-FU, carboplatin and cisplatin.
  • the chemotherapeutic agent may be administered as a single agent or in combination with other chemotherapeutic agents.
  • the doses of chemotherapeutic agent(s) administered in combination other chemotherapeutic agents are according to Category 1 recommendations in National Comprehensive Cancer Network treatment guidelines.
  • the dosage regimen of the chemotherapeutic agent(s) is as per local standard of care. It is to be understood that where mg/ m 2 is used, this is mg/ m 2 of body surface.
  • docetaxel is administered at a dose of about 30 mg/m 2 . In one embodiment, docetaxel is administered at a dose of about 75 mg/m 2 . In one embodiment, docetaxel is administered at a dose of about 100 mg/m 2 . In one embodiment, docetaxel is administered via IV infusion.
  • docetaxel is administered via IV infusion over 1 hour. In one embodiment, docetaxel is administered once every three weeks. In one embodiment, docetaxel is administered once every three weeks for 1, 2, 3, 4, 5 or 6 cycles, . In one embodiment, 30 mg/m 2 docetaxel is administered weekly for 5 weeks in a 6 week cycle for up to 5 cycles. In one embodiment, docetaxel is administered at a dose of about 75 mg/m 2 once every three weeks for up to 10 cycles. In one embodiment, docetaxel is administered at a dose of about 75 mg/m 2 once every three weeks via IV infusion. In one embodiment, pemetrexed is administered at a dose of about 500 mg/m 2 . In one embodiment, pemetrexed is administered via IV infusion.
  • pemetrexed is administered once every three weeks. In one embodiment, pemetrexed is administered at a dose of about 500 mg/m 2 once every three weeks via IV infusion. In one embodiment, paclitaxel is administered at a dose of about 135 mg/m 2 to about 225 mg/m 2 . In one embodiment, paclitaxel is administered at a dose of about 175 mg/m 2 . In one embodiment, paclitaxel is administered at a dose of about 200 mg/m 2 . In one embodiment, paclitaxel is administered at a dose of about 225 mg/m 2 . In one embodiment, paclitaxel is administered via IV infusion. In one embodiment, paclitaxel is administered via IV infusion over 3 hours.
  • paclitaxel is administered once every three weeks. In one embodiment, paclitaxel is administered once every three weeks for up to 8 cycles, (i.e. 1, 2, 3, 4, 5, 6, 7 or 8 cycles). In one embodiment, paclitaxel is administered at a dose of about 200 mg/m 2 once every three weeks via IV infusion. In one embodiment, paclitaxel is administered at a dose of about 135 mg/m 2 to 175 mg/m 2 every three weeks. In one embodiment, gemcitabine is administered at a dose of about 1000 mg/m 2 to about 1250 mg/m 2 . In one embodiment, gemcitabine is administered at a dose of about 1250 mg/m 2 . In one embodiment, gemcitabine is administered via IV infusion.
  • gemcitabine is administered on Days 1 and 8 of each 21 day cycle (Q3W). In one embodiment, gemcitabine is administered on Days 1, 8 and 15 of each 28 day cycle (Q4W).In one embodiment, gemcitabine is administered in a 4 week cycle, wherein it is administered once weekly for 3 weeks followed by a 1 week rest period. In one embodiment, gemcitabine is administered in a 8 week cycle, wherein gemcitabine is adminstered weekly for 7 weeks followed by a week of rest. In one embodiment, gemcitabine is administered once every three weeks. In one embodiment, gemcitabine is administered at a dose of about 1250 mg/m 2 once every three weeks via IV infusion.
  • 5-FU is administered at a dose of about 200 mg/m 2 to about 1200 mg/m 2 . In one embodiment, 5-FU is administered at a dose of about 200 mg/m 2 to about 1000 mg/m 2 . In one embodiment, 5-FU is administered at a dose of about 200 mg/m 2 to about 600 mg/m 2 . In one embodiment, 5-FU is administered at a dose of about 200 mg/m 2 to about 500 mg/m 2 . In one embodiment, 5-FU is administered at a dose of about 500 mg/m 2 to about 600 mg/m 2 . In one embodiment, 5-FU is administered at a dose of about 200 mg/m 2 . 5-FU may administered as a continuously over several days. In such cases, the unit mg/m 2 /day is used.
  • 5-FU is administered at a dose of about 1000 mg/m 2 to about 1200 mg/m 2 /day. In one embodiment, 5-FU is administered at a dose of about 1000 mg/m 2 /day. In one embodiment, 5-FU is administered via IV infusion. In one embodiment, 5-FU is administered on Day 1 through Day 4 of every 21-day cycle (Q3W). In one embodiment 5-FU is administered once every week. In one embodiment 5-FU is administered once every 3 weeks. In one embodiment 5-FU is administered once every 4 weeks. In one embodiment 5-FU is administered montly or bimonthy. In one embodiment, 5-FU is administered at a dose of about 1000 mg/m 2 /day on Day 1 through Day 4 of every 21-day cycle (Q3W) via IV infusion.
  • Q3W 21-day cycle
  • carboplatin is administered at a dose of about AUC 4-7 mg/ml per min. In one embodiment, carboplatin is administered at a dose of about AUC 4-6 mg/ml per min. In one embodiment, carboplatin is administered at a dose of about AUC 5 mg/ml per min. In one embodiment, carboplatin is administered at a dose of about 300 mg/m 2 to about 360 mg/m 2 . In one embodiment, carboplatin is administered via IV infusion. In one embodiment, carboplatin is administered intraperitoneally. In one embodiment, carboplatin is administered once every three weeks. In one embodiment, carboplatin is administered once every 4 weeks.
  • carboplatin is administered at a dose of about AUC 4-6 mg/ml per min once every three weeks via IV infusion. In one embodiment, carboplatin is administered at a dose of about 300 mg/m 2 to about 360 mg/m 2 once every 4 weeks via IV infusion. In one embodiment, cisplatin is administered at a dose of about 20 mg/m 2 to about 120 mg/m 2 . In one embodiment, cisplatin is administered at a dose of about 20 mg/m 2 . In one embodiment, cisplatin is administered at a dose of about 40 mg/m 2 . In one embodiment, cisplatin is administered at a dose of about 100 mg/m 2 . In one embodiment, docetaxel is administered via IV infusion.
  • cisplatin is administered once every three weeks (Q3W). In one embodiment, cisplatin is administered once every 4 weeks. In one embodiment, cisplatin is administered once every week for 6 weeks. In one embodiment, cisplatin is administered at a dose of about 75 mg/m 2 once every three weeks via IV infusion. In one embodiment, cisplatin is administered at a dose of 75 mg/m 2 to about 100 mg/m 2 once every four weeks or about 50 mg/m 2 to about 70 mg/m 2 once every three to four weeks once every three weeks via IV infusion. In some embodiments, a combination (e.g. doublet) of chemotherapeutic agents may be administered.
  • the combination of chemotherapeutic agents is carboplatin and one of pemetrexed or paclitaxel or gemcitabin or fluorouracil. In one embodiment, the combination of chemotherapeutic agents is carboplatin and pemetrexed. In one embodiment, the combination of chemotherapeutic agents is carboplatin and paclitaxel. In one embodiment, the combination of chemotherapeutic agents is carboplatin and gemcitabin. In one embodiment, the ocmbination of chemotherapeutic agents is carboplatin and fluorouracil. In one embodiment, the combination of chemotherapeutic agents is cisplatin and one of pemetrexed or paclitaxel or gemcitabin or fluorouracil.
  • the combination of chemotherapeutic agents is cisplatin and pemetrexed. In one embodiment, the combination of chemotherapeutic agents is cisplatin and paclitaxel. In one embodiment, the combination of chemotherapeutic agents is cisplatin and gemcitabin. In one embodiment, the combination of chemotherapeutic agents is cisplatin and fluorouracil.
  • the carboplatin chemotherapy doublets may calculate the dose of carboplatin according to Calvert formula using the target dose of about AUC of 4-6 mg/ml per min as per local standard of care in combination with one of i) pemetrexed at a dose of about 500 mg/m 2 ; ii) gemcitabine at a dose of about 1250 mg/m 2 ; and iii) paclitaxel at a dose of about 200 mg/m 2 .
  • the combination of chemotherapeutic agents is a platinum-based chemotherapy doublet.
  • the platinum-based chemotherapy doublet is 5-FU and carboplatin or cisplatin.
  • the platinum-based chemotherapy doublet is 5-FU and carboplatin.
  • the platinum-based chemotherapy doublet is 5-FU and cisplatin.
  • 5-FU is administered at a dose of about 1000 mg/m 2 and carboplatin is administered at a dose of about AUC 5 mg/ml per min.
  • 5-FU is administered at a dose of about 1000 mg/m 2 and cisplatin is administered at a dose of about 100 mg/m 2 .
  • Cancer The therapeutic agent(s) and methods of the invention may be used in the treatment of cancer. By the term “treating" and grammatical variations thereof as used herein, is meant therapeutic therapy.
  • treating means: (1) to ameliorate, or lessen the severity of, 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 or signs, effects or side effects associated with the condition or treatment thereof, (4) to slow the progression of the condition, that is to say prolong survival, 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 As used herein, the terms “cancer”, “neoplasm”, “malignancy”, and “tumor” are used interchangeably and, in either the singular or plural form, refer 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
  • 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.”
  • liquid 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.
  • leukemias 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 thrombocytosis), and polcythemia vera (PCV).
  • CML chronic myelogenous leukemia
  • CMML chronic myelomonocytic leukemia
  • PCV polcythemia vera
  • 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.
  • 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.
  • B-cell malignancies 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), Waldenström’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
  • Waldenström’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.
  • the treatment of cancer is first-line treatment of cancer.
  • the treatment of cancer is second-line treatment of cancer.
  • the treatment is third-line treatment of cancer.
  • the treatment is fourth-line treatment of cancer.
  • the treatment is fifth-line treatment of cancer.
  • prior treatment to said second-line, third-line, fourth-line or fifth-line treatment of cancer comprises one or more of radiotherapy, chemotherapy, surgery or radiochemotherapy.
  • the cancer is selected from: brain cancer, glioblastomas, glioma (such as diffuse intrinsic pontine glioma), Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer (e.g. inflammatory breast cancer), Wilm's tumor, ependymoma, medulloblastoma, cardiac tumors, colon cancer, colorectal cancer, head and neck cancer (e.g.
  • squamous cell carcinoma of the head and neck cancer of the mouth (i.e. oral cancer), salivary gland cancer, buccal cancer, pharyngeal cancer, oropharyngeal cancer, nasopharangeal cancer, hypopharyngeal cancer, laryngeal cancer), eye cancer (e.g. retinoblastoma), lung cancer (e.g. non- small cell lung cancer, small cell cancer), liver cancer (i.e. hepatocellular cancer), skin cancer (e.g. basal cell carcinoma, merkel cell carcinoma, squamous cell carcinoma), melanoma, ovarian cancer, pancreatic cancer, bile duct cancer, gallbladder cancer, prostate cancer, sarcoma (e.g.
  • 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 leukemia, mantle cell leukemia, multiple myeloma megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant
  • rectal cancer bladder cancer, urothelial cancer, urethral cancer, vaginal cancer, vulvar cancer, cervical cancer, endometrial cancer, uterine cancer, fallopian tube cancer, renal cancer (i.e. kidney cancer, e.g. renal cell carcinoma), mesothelioma (e.g. malignant pleural mesothelioma), esophageal cancer (e.g. esophageal squamous cell carcinoma), gastric cancer (i.e. stomach cancer), gastroinstestinal carcinoid tumor, GIST (gastrointestinal stromal tumor), appendicial cancer, penile cancer, testicular cancer, germ cell tumors.
  • the cancer exhibits microsatellite instability (MSI).
  • Microsatellite instability is or comprises a change that in the DNA of certain cells (such as tumor cells) in which the number of repeats of microsatellites (short, repeated sequences of DNA) is different than the number of repeats that was contained in the DNA from which it was inherited.
  • Microsatellite instability arises from a failure to repair replication-associated errors due to a defective DNA mismatch repair (MMR) system. This failure allows persistence of mismatch mutations all over the genome, but especially in regions of repetitive DNA known as microsatellites, leading to increased mutational load. It has been demonstrated that at least some tumors characterized by MSI-H have improved responses to certain anti-PD-1 agents (Le et al. (2015) N. Engl. J.
  • a cancer has a microsatellite instability status of high microsatellite instability (e.g. MSI-H status). In some embodiments, a cancer has a microsatellite instability status of low microsatellite instability (e.g. MSI-L status). In some embodiments, a cancer has a microsatellite instability status of microsatellite stable (e.g. MSS status).
  • microsatellite instability status is assessed by a next generation sequencing (NGS)-based assay, an immunohistochemistry (IHC)-based assay, and/or a PCR-based assay.
  • NGS next generation sequencing
  • IHC immunohistochemistry
  • PCR PCR-based assay.
  • microsatellite instability is detected by NGS.
  • microsatellite instability is detected by IHC.
  • microsatellite instability is detected by PCR.
  • the cancer is associated with a high tumor mutation burden (TMB).
  • TMB tumor mutation burden
  • the cancer is associated with high TMB and MSI-H.
  • the cancer is associated with high TMB and MSI-L or MSS.
  • the cancer is endometrial cancer associated with high TMB.
  • the endometrial cancer is associated with high TMB and MSI-H. In some related embodiments, the endometrial cancer is associated with high TMB and MSI-L or MSS.
  • a cancer is a mismatch repair deficient (dMMR) cancer. Microsatellite instability may arise from a failure to repair replication-associated errors due to a defective DNA mismatch repair (MMR) system. This failure allows persistence of mismatch mutations all over the genome, but especially in regions of repetitive DNA known as microsatellites, leading to increased mutational load that may improve responses to certain therapeutic agents.
  • a cancer is a hypermutated cancer.
  • a cancer harbors a mutation in polymerase epsilon (POLE). In some embodiments, a cancer harbors a mutation in polymerase delta (POLD). In some embodiments, the cancer is an advanced cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is a recurrent cancer (e.g. a recurrent gynecological cancer such as recurrent epithelial ovarian cancer, recurrent fallopian tube cancer, recurrent primary peritoneal cancer, or recurrent endometrial cancer). In one embodiment, the cancer is recurrent or advanced. In some embodiments, the cancer is current/metastatic (R/M).
  • R/M current/metastatic
  • the cancer is recurring/refectory (R/R).
  • the human has a liquid tumor such as diffuse large B cell lymphoma (DLBCL), multiple myeloma, chronic lymphoblastic leukemia, follicular lymphoma, acute myeloid leukemia and chronic myelogenous leukemia.
  • 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 or HNSCC), gastric cancer, melanoma, mesothelioma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma (NSCLC), prostate cancer, esophageal cancer, esophageal squamous cell carcinoma, colorectal cancer, cervical cancer, bladder cancer, urothelial cancer, ovarian cancer and pancreatic cancer.
  • SCCHN or HNSCC squamous cell carcinoma of the head and neck
  • gastric cancer melanoma
  • mesothelioma mesothelioma
  • RRCC renal cell carcinoma
  • NSCLC non-small cell lung carcinoma
  • prostate cancer esophageal cancer, esophageal squamous cell carcinoma, colorectal cancer, cervical cancer, bladder cancer, urothelial cancer, ovarian cancer and pancreatic cancer.
  • the human has one or more of the following: HNSCC, colorectal cancer, esophageal cancer, cervical cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, melanoma, renal cell carcinoma (RCC), esophageal squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma (e.g. pleural malignant mesothelioma), urothelial cancer and prostate cancer.
  • the renal cell carcinoma is advanced renal cell carcinoma.
  • the cancer is head and neck cancer.
  • the cancer is HNSCC.
  • Squamous cell carcinoma is a cancer that arises from particular cells called squamous cells.
  • HNSCC Head and neck squamous cell carcinoma
  • Squamous cells are found in the outer layer of skin and in the mucous membranes, which are the moist tissues that line body cavities such as the airways and intestines.
  • Head and neck squamous cell carcinoma develops in the mucous membranes of the mouth, nose, and throat.
  • HNSCC can occur in the mouth (oral cavity), the middle part of the throat near the mouth (oropharynx), the space behind the nose (nasal cavity and paranasal sinuses), the upper part of the throat near the nasal cavity (nasopharynx), the voicebox (larynx), or the lower part of the throat near the larynx (hypopharynx).
  • the cancer can cause abnormal patches or open sores (ulcers) in the mouth and throat, unusual bleeding or pain in the mouth, sinus congestion that does not clear, sore throat, earache, pain when swallowing or difficulty swallowing, a hoarse voice, difficulty breathing, or enlarged lymph nodes.
  • HNSCC can metastasize to other parts of the body, such as the lymph nodes, lungs or liver. Tobacco use and alcohol consumption are the two most important risk factors for the development of HNSCC, and their contributions to risk are synergistic.
  • the human papillomavirus (HPV), especially HPV-16 is now a well-established independent risk factor. Patients with HNSCC have a relatively poor prognosis.
  • Recurrent/metastatic (R/M) HNSCC is especially challenging, regardless of human papillomavirus (HPV) status, and currently, few effective treatment options are available in the art.
  • HPV-negative HNSCC is associated with a locoregional relapse rate of 19–35% and a distant metastatic rate of 14–22% following standard of care, compared with rates of 9–18% and 5–12%, respectively, for HPV-positive HNSCC.
  • the median overall survival for patients with R/M disease is 10–13 months in the setting of first-line chemotherapy and 6 months in the second-line setting.
  • the current standard of care is platinum-based doublet chemotherapy with or without cetuximab.
  • Second-line standard of care options include cetuximab, methotrexate, and taxanes. All of these chemotherapeutic agents are associated with significant side effects, and only 10–13% of patients respond to treatment. HNSCC regressions from existing systemic therapies are transient and do not add significantly increased longevity, and virtually all patients succumb to their malignancy.
  • the cancer is recurrent/metastatic (R/M) HNSCC. In one embodiment, the cancer is recurring/refractory (R/R) HNSCC. In one embodiment, the cancer is HPV-negative or HPV-positive HNSCC. In one embodiment, the cancer is a locally advanced HNSCC.
  • the cancer is (R/M) HNSCC in PD-L1 CPS (Combined Positive Score) positive (CPS 31) patients.
  • the combined positive score is as determined by an FDA-approved test.
  • PD-L1 CPS is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.
  • PD-L1 CPS is determined using PharmDx 22C3
  • the cancer is HNSCC in PD-1 binding protein/PD-L1 binding protein experienced or PD-1 binding protein/PD-L1 binding protein na ⁇ ve patients.
  • the cancer is HNSCC in PD-1 binding protein/PD-L1 binding protein experienced or PD-1 binding protein/PD-L1 binding protein na ⁇ ve patients.
  • the head and neck cancer is oropharyngeal cancer.
  • the head and neck cancer is an oral cancer (i.e. a mouth cancer).
  • the treatment is first-line or second line treatment of HNSCC.
  • the treatment is first-line or second line treatment of recurrent/metastatic HNSCC.
  • the treatment is first line treatment of recurrent/metastatic (1L R/M) HNSCC.
  • the treatment is first line treatment of 1L R/M HNSCC in a PD-L1 CPS (combined positive score) positive (CPS 31) patients.
  • the treatment is second line treatment of recurrent/metastatic (2L R/M) HNSCC.
  • the treatment is first-line, second-line, third-line, fourth-line or fifth-line treatment of PD-1/PD-L1-na ⁇ ve HNSCC.
  • the treatment first-line, second-line, third-line, fourth-line or fifth-line treatment of PD-1/PD-L1 experienced HNSCC.
  • the cancer is lung cancer.
  • the lung cancer is a squamous cell carcinoma of the lung.
  • the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as squamous NSCLC. In some embodiments, the lung cancer is an ALK-translocated lung cancer (e.g. ALK-translocated NSCLC). In some embodiments, the cancer is NSCLC with an identified ALK translocation. In some embodiments, the lung cancer is an EGFR-mutant lung cancer (e.g. EGFR- mutant NSCLC). In some embodiments, the cancer is NSCLC with an identified EGFR mutation. In one embodiment, the cancer is advanced NSCLC. In another embodiment, the cancer is relapsed/refractory advanced NSCLC.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • ALK-translocated lung cancer e.g. ALK-translocated NSCLC
  • the cancer is NSCLC with an identified ALK translocation.
  • the lung cancer is an EGFR-mutant lung cancer (e
  • the cancer is melanoma.
  • the melanoma is an advanced melanoma.
  • the melanoma is a metastatic melanoma.
  • the melanoma is unresectable or metastatic melanoma.
  • the melanoma is adjuvant melanoma.
  • the melanoma is a MSI-H melanoma.
  • the melanoma is a MSS melanoma.
  • the melanoma is a POLE-mutant melanoma.
  • the melanoma is a POLD-mutant melanoma. In some embodiments, the melanoma is a high TMB melanoma. In one embodiment, the cancer is urothelial cancer. In some embodiments, the urothelial cancer is an advanced urothelial cancer. In some embodiments, the urothelial cancer is a metastatic urothelial cancer. In some embodiments, the urothelial cancer is a MSI-H urothelial cancer. In some embodiments, the urothelial cancer is a MSS urothelial cancer. In some embodiments, the urothelial cancer is a POLE-mutant urothelial cancer.
  • the urothelial cancer is a POLD- mutant urothelial cancer. In some embodiments, the urothelial cancer is a high TMB urothelial cancer.
  • the following examples are intended for illustration only, and are not intended to limit the scope of the invention in any way.
  • EXAMPLES Example 1 The following study evaluated tumor growth inhibition efficacy of the surrogate murine ICOS IgG1 clone 7E.17G9 antibody in combination with an anti-mouse CTLA-4 clone 9H10 antibody in EMT- 6 syngeneic tumor model. EMT-6 murine breast carcinoma cell line readily form tumors in wild type BALB/c mice with intact immune systems and is routinely used as a model to evaluate anti-cancer immunotherapies.
  • mice were six week old female Balb/c mice (BALB/cAnNHsd, Envigo).
  • Cell line culture EMT-6 were obtained from the American Type Culture Collection (ATCC) and cultured in flasks in a humidified incubator at 37°C with 5% CO2.
  • ATCC American Type Culture Collection
  • Cells were expanded and cryopreserved in multiple vials and stored at vapor phase of liquid nitrogen for future use.
  • Cryopreserved cells stocks were negative for mouse pathogens.
  • One vial of cells was thawed and cultured for additional 3 passages prior to tumor inoculation.
  • mice were randomized into various groups based on tumor volume using stratified sampling method in the StudyLog software prior to initiation of treatment. ANOVA results were displayed to ensure similarity between groups (a p value >0.99). Observations and Endpoints Post EMT-6 inoculation, the animals were checked daily for any effects of tumor growth and treatments on behaviour such as mobility, food and water consumption, and general clinical observations. Tumor size and body weight was measured 2-3 times per week, and individual animals were euthanized when tumor reached a pre-determined endpoint (tumor volume of > 2000 mm3, ulceration, body weight loss >20%) or at the end of the study, whichever came first.
  • Kaplan-Meier (KM) survival analysis Method is carried out to estimate the survival probability of different treatment groups at a given time. The median time to endpoint and its corresponding 95% confidence interval is reported. Whether or not KM survival curves are statistically different between any two groups is then tested by log-rank test. p-values are adjusted for multiplicity using the FDR (false discovery rate) method.
  • aICOS in combination with aCTLA-4 did not result in statistically significant tumor growth inhibition or survival advantage compared to the efficacious aCTLA-4 monotherapy.
  • a trend of combination enhanced survival was observed compared to CTLA-4 monotherapy however, in that the aICOS + aCTLA-4 combination resulted in 9 tumor free mice compared to 4 for aICOS + isotype and 7 for aCTLA-4 + isotype monotherapies.
  • ICOS is a T-cell specific CD28-superfamily costimulatory molecule and immune checkpoint protein which is expressed on certain activated T cells and plays a key role in the proliferation and activation of T cells.
  • ICOS mouse IgG1 clone 7E.17G9 is the surrogate agonistic antibody targeting and binding to ICOS expressed on murine T cells.
  • the mouse IgG1 isotype corresponds to the ICOS human IgG4 (H2L5 IgG4PE) antibody in regard to Fc interaction in the mouse.
  • 7E.17G9 expressed on a mouse IgG1 isotype interacts with FcgRIIb Fc receptors to enable ICOS receptor cross- linking without antibody-dependent cell-mediated cytotoxicity (ADCC).
  • the objective of this study was to evaluate tumor growth inhibition efficacy of the surrogate murine ICOS IgG1 clone 7E.17G9 antibody in combination with the anti-mouse CTLA-4 clone 9H10 antibody in the EMT-6 syngeneic tumor model.
  • ICOS in combination with anti-CTLA-4 showed a trend of combination benefit in that the total number of tumor free mice increased with the combinations, versus the most efficacious monotherapy.
  • H2L5 IgG4PE is a humanized IgG4 antibody selected for its potent binding, agonist activity against human ICOS and low/no depleting effects.
  • the unique mechanistic profile of H2L5 IgG4PE offers an opportunity to investigate the antitumor potential of targeting a T cell co-stimulator alone and in combination with standard-of-care (SoC) agents.
  • H2L5 IgG4PE comprises CDR sequences as shown in SEQ ID NOS: 1-6, variable heavy chain and variable light chain sequences as shown in SEQ ID NO:7 and SEQ ID NO: 8, respectively, and heavy chain and light chain sequences as shown in SEQ ID NO:9 and SEQ ID NO:9, respectively.
  • PK pharmacokinetics
  • PD pharmacodynamics
  • H2L5 IgG4PE comprises CDR sequences as shown in SEQ ID NOS: 1-6, variable heavy chain and variable light chain sequences as shown in SEQ ID NO:7 and SEQ ID NO: 8, respectively, and heavy chain and light chain sequences as shown in SEQ ID NO:9 and SEQ ID NO:9, respectively.
  • the objectives of the study are as follows: Primary ⁇ Determine safety, tolerability, and maximum tolerated/administered dose of H2L5 IgG4PE. Secondary ⁇ Determine recommended H2L5 IgG4PE dose(s) for further exploration. ⁇ Evaluate preliminary antitumor activity; characterize PK; evaluate immunogenicity. Exploratory ⁇ Evaluate PD effects. ⁇ Explore associations between antitumor activity, PK and biomarkers in tissue and blood. Methods The Study is a dose escalation (DE) and ongoing expansion phase study of H2L5 IgG4PE.. Modified toxicity probability interval informed DE decisions with 3 3 patients enrolled per dose level (DL).
  • DE dose escalation
  • DL dose level
  • H2L5 IgG4PE is administered as intravenous infusion every 3 weeks (Q3W); treatment continues up to 2 years or until progression or unacceptable toxicity. Patients must have metastatic or relapsed invasive malignancy, measurable disease, received £ 5 lines of prior therapy in the advanced setting, adequate organ function, and no active autoimmune disease requiring treatment; PK/PD cohorts require pre- treatment and Day 43 on-treatment tumor biopsies. Primary objective is to determine safety, tolerability, and maximum tolerated (MTD) H2L5 IgG4PE dose.
  • tumour types ⁇ Bladder/urothelial cancer of the upper and lower urinary tract ⁇ Cervical ⁇ Colorectal (includes appendix) (microsatellite stability (MSS)/ high microsatellite instability (MSI-H)) ⁇ Esophageal squamous cell carcinoma ⁇ Head and Neck Carcinoma (any histology) ⁇ Melanoma (cutaneous/ocular) ⁇ MPM ⁇ NSCLC (including targeted mutations) ⁇ Prostate ⁇ MSI-H/dMMR tumor (Part 1B) ⁇ HPV-positive or EBV-positive tumor (Part 1B) ⁇ Malignant pleural mesothelioma ⁇ Disease that has progressed after standard therapy for the specific tumor type, or for which standard therapy has proven to be ineffective, is intolerable, or is
  • Central nervous system (CNS) metastasis ⁇ Central nervous system (CNS) metastasis; exceptions include previously treated CNS metastasis that is asymptomatic and has no requirement for steroids at least 14 days prior to first dose of study treatment.
  • ⁇ Active autoimmune disease that required systemic treatment within the last 2 years.
  • the study design involves ⁇ Accelerated titration design for the first 3 dose levels; 1 patient enrolled at each dose level.
  • Modified toxicity probability interval method informed subsequent dose escalation decisions (minimum 3 patients per dose level).
  • Starting dose of 0.001 mg/kg the projected human dose based on the minimally anticipated biologic effect observed in preclinical studies.
  • the study consists of a dose escalation phase followed by a cohort expansion phase.
  • This is a FTIH, open-label, multicenter study designed to investigate the safety, tolerability, pharmacology, PK, preliminary clinical activity, and establish a recommended dose of H2L5 IgG4PE for further exploration.
  • the study consists of a dose escalation (Part 1A) phase followed by a cohort expansion phase (Part 1B).
  • the dose escalation phase evaluates escalating weight-based dose levels of H2L5 IgG4PE administered intravenously once every three weeks (Q3W) to subjects with selected relapsed and/or refractory solid tumors.
  • expansion cohorts may initiate with H2L5 IgG4PE weight-based dosing, a transition to fixed dosing may be made.
  • Seamless design is implemented to combine dose escalation with dose expansion, based on toxicity and efficacy (Pan H, Fang X, Liu P, et al. A phase I/II seamless dose escalation/expansion with adaptive randomization scheme (SEARS). Clinical Trials. 2013; 0:1-11).
  • SEARS adaptive randomization scheme
  • Randomization and/or futility rules may be incorporated if appropriate in expansion phase to optimize the dose allocation based on evaluations of safety and antitumor activity.
  • the details of randomization schema for expansion cohorts will be documented before the initiation of expansion cohort; details of the futility rules will be documented in the RAP before initiation of interim analyses (Pan H, Fang X, Liu P, et al. A phase I/II seamless dose escalation/expansion with adaptive randomization scheme (SEARS). Clinical Trials. 2013; 0:1-11). The study will enroll subjects diagnosed with solid tumor malignancies.
  • the solid tumor types selected for inclusion include bladder/urothelial cancer, cervical cancer, colorectal cancer (CRC), esophageal cancer with squamous cell histology, head and neck (HN) cancer, melanoma, malignant pleural mesothelioma (MPM), non-small-cell lung cancer (NSCLC), and prostate cancer.
  • ⁇ In the cohort expansion phases of the study, several expansion cohorts have been defined by tumor histology or by a specific characteristic such as tumors exhibiting high microsatellite instability (MSI-H), deficiency in DNA mismatch repair (dMMR) processes, or viral-mediated pathology; enrollment in these cohorts is not limited to the tumor types/histologies in the aforementioned list (defined as tumor agnostic).
  • Additional expansion cohorts may enroll subjects with a specific tumor type selected from the aforementioned list or from a tumor type/histology not protocol-defined; the basis for the selection will be evidence-based and by an amendment to the protocol to define the cohorts.
  • the overall study size may extend beyond 500 by a protocol amendment if data from expansion phases support extended enrollment or additional combinations are investigated.
  • Therapeutic monoclonal antibodies are often dosed based on body-size due to the concept that this reduces inter-subject variability in drug exposure.
  • body-weight dependency of PK parameters does not always explain the observed variability in the exposure of monoclonal antibodies (Zhao X, Suryawanshi, S; Hruska, M. Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3 mg/kg dosing regimen in patient with advanced tumors. Annals of Oncology. 2017;28:2002-2008).
  • the advantage of body-weight based versus fixed dosing in this study was evaluated through population PK modelling and simulation efforts.
  • Table 6 shows treatment-related AEs (in >3 patients).
  • Table 6 AE - Adverse Event; AST – Aspartate Aminotransferase; TR-AE – Treatment-related AE.
  • Treatment-related safety ⁇ 1 patient in monotherapy dose escalation cohort experienced Grade 3/4 elevations in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, gamma-glutamyl transpeptidase, impaired liver function (serious) and Grade 1 amylase and G3 lipase.
  • SAEs Serious adverse events in monotherapy group: 1 patient (3 mg/kg) had impaired liver function (Grade 3).
  • Tumor biopsies collected after 43 days on-treatment showed greater number of T cells, granzyme-B expressing CD8 Tc cells, PD1 expressing T cells and proliferating T cells while fewer proliferating tumor cells (data not shown).
  • Patient 2 H2L5 IgG4PE monotherapy History: ⁇ BRAF negative, N/KRAS mutation positive; Stage Ib superficial spreading melanoma.
  • Prior regimens nivolumab (advanced/metatstatic) ⁇ 10 months; Electrochemotherapy.
  • Study treatment ⁇ H2L5 IgG4PE monotherapy at 1 mg/kg.
  • the post treatment sample showed: ⁇ Higher TIL including cytotoxic, helper T cells and NK cells ⁇ More Granzyme B+ T cells and less proliferating tumour cells ⁇ Increase in activated T cells as observed with greater OX40 and HLADR expression ⁇ Upregulation of PD1 and PD-L1 upon H2L5 IgG4PE treatment Conclusions ⁇ H2L5 IgG4PE was well tolerated in patients with advanced solid tumours at the 0.001–3 mg/kg dose range. ⁇ Maximum tolerated dose was not reached; maximum administered dose was 3 mg/kg H2L5 IgG4PE. ⁇ Majority of AEs were Grade 1/2 and not attributed to study treatment.
  • ⁇ AEs leading to discontinuation occurred in 1 patient (n 62 patients) at the highest dose level.
  • ⁇ PK/PD analysis showed 375% total ICOS receptor saturation across dosing interval at H2L5 IgG4PE dose levels 30.3 mg/kg.
  • ⁇ A range of doses (30.1–1 mg/kg) have shown biological and clinical activity (including in patients with prior anti-PD-1/L1 exposure). These doses are being investigated further in expansion cohorts to establish the recommended H2L5 IgG4PE dose.
  • Preliminary biological and clinical data support the mechanism of action of a non-depleting ICOS agonist as a clinical target.
  • Example 3 describes pharmacokinetics/pharmacodynamics (PK/PD) exposure-response characterization of H2L5 IgG4PE from the study described in Example 1.
  • H2L5 IgG4PE is an agonist IgG4PE antibody against inducible co-stimulatory receptor (ICOS) with immune stimulating and anti- neoplastic activity.
  • the study described Example 2 is the first in human study investigating H2L5 IgG4PE.
  • PK Analysis A preliminary population PK data set was constructed with all pooled concentration–time data ⁇ Serial plasma samples were collected throughout; PK samples were assayed by validated ELISA assay and concentration–time data was modeled using nonlinear mixed effects, as implemented in NONMEM.
  • Pharmacodynamic (PD) Analysis ⁇ Flow cytometry was performed instream throughout the study to evaluate ICOS receptor occupancy (RO) with H2L5 IgG4PE.
  • RO ICOS receptor occupancy
  • tumor tissue was collected at pre-dose and at Week 6 for evaluation of overall TIL, changes in activation, proliferation and gene expression changes.
  • Exposure measure for PK/PD analyses defined as Week 6 pre-dose trough concentration derived from population PK model.
  • FIGS. 2A and 2B are plots showing duration of H2L5 IgG4PE monotherapy treatment: individual patient data.
  • Figure 2A shows monotherapy dose escalation cohort.
  • Figure 2B shows PK/PD cohort. Results The PK disposition of H2L5 IgG4PE is consistent with that of other humanized mAbs, with low clearance and limited central volume of distribution.
  • H2L5 IgG4PE is a humanized IgG4 antibody selected for its potent binding, agonist activity against human ICOS and low/no depleting effects.
  • the unique mechanistic profile of H2L5 IgG4PE offers an opportunity to investigate the antitumor potential of targeting a T cell co-stimulator alone and in combination with ipilimumab.
  • H2L5 IgG4PE comprises CDR sequences as shown in SEQ ID NOS: 1-6, and variable heavy chain and variable light chain sequences as shown in SEQ ID NO:7 and SEQ ID NO: 8, respectively.
  • SSCLC non-small cell lung cancer
  • ipilimumab The 1 or 3 mg/kg doses for ipilimumab were selected based on approvals in multiple tumor types, both as monotherapy and in combinations with PD-L1 inhibitors.
  • Ipilimumab is currently approved as monotherapy in unresectable or metastatic melanoma at a dose of 3 mg/kg every 3 weeks and adjuvant melanoma at 10 mg/kg every 3 weeks.
  • ipilimumab is approved in combination with nivolumab in advanced renal cell carcinoma, microsatellite instability-high/ mismatch repair deficient metastatic colon cancer, hepatocellular carcinoma, and metastatic non-dmall cell lung cancer at approved doses of either 1 or 3 mg/kg administered ever 2 or 3 weeks based on indication.
  • the Q3W dosing frequency for ipilimumab matches the dosing frequency for H2L5 IgG4PE (Q3W) providing greater patient convenience.
  • Study Intervention The route of administration for all agents is IV.
  • H2L5 IgG4PE is to be administered first as an IV infusion over 30 minutes.
  • Ipilimumab will be administered as a 90 minute IV infusion beginning at least 30 minutes and no more than 2 hours following the end of the H2L5 IgG4PE infusion. Infusion time of each may be adjusted based on infusion-related reactions. Administration will be until up to 2 years, progressive disease or unacceptable toxicity.
  • the dose may be reduced to 1 mg/kg or the frequency of dosing to once every 6 weeks (Q6W).
  • Q6W the frequency of dosing of ipilimumab may be altered to once every 6 weeks (Q6W).

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Abstract

La présente invention concerne une méthode de traitement du cancer chez un être humain en ayant besoin, le procédé comprenant l'administration à l'être humain d'une protéine de liaison d'ICOS agoniste ou d'une partie de liaison à l'antigène de celle-ci à une dose d'environ 0,08 mg à environ 240 mg et l'administration d'ipilimumab à l'être humain.
PCT/US2020/049317 2019-09-06 2020-09-04 Schéma posologique pour le traitement du cancer avec un anticorps agoniste anti-cos et de l'ipilimumab WO2021046289A1 (fr)

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