EP2729174A1 - Antagonistes de l'il-23 utilisables en vue du traitement ou de la prévention d'éruptions cutanées associées à un traitement par des inhibiteurs de la voie pi3k/akt - Google Patents

Antagonistes de l'il-23 utilisables en vue du traitement ou de la prévention d'éruptions cutanées associées à un traitement par des inhibiteurs de la voie pi3k/akt

Info

Publication number
EP2729174A1
EP2729174A1 EP12811568.0A EP12811568A EP2729174A1 EP 2729174 A1 EP2729174 A1 EP 2729174A1 EP 12811568 A EP12811568 A EP 12811568A EP 2729174 A1 EP2729174 A1 EP 2729174A1
Authority
EP
European Patent Office
Prior art keywords
antibody
antagonist
seq
phenyl
sequence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12811568.0A
Other languages
German (de)
English (en)
Inventor
Svetlana Sadekova
Robert H PIERCE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme LLC
Publication of EP2729174A1 publication Critical patent/EP2729174A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the present invention relates generally to methods of treating and/or preventing side effects of treatment with PI3K/AKT pathway inhibitors, such as skin rash resulting from cancer therapy.
  • Cancer is often treated with agents that selectively disrupt the proliferation of malignant cells. Such agents, however, can cause unwanted side effects. Such side effects can be dose-limiting if the agent must be dosed at sub-optimal levels to avoid unacceptable side effects. Such dose-limiting toxicities (“DLT”) may prevent treatment of cancer patients at high enough doses to be efficacious, reducing the usefulness of an otherwise effective drug.
  • DLT dose-limiting toxicities
  • PI3K/AKT pathway provide one example.
  • the PI3K/AKT pathway appears to be important for regulating cell survival/cell death (Kulik et al. (1997) Mol. Cell. Biol. 17:1595- 1606; Franke et al. (1997) Cell 88:435-437; Kauffmann Zeh et al. (1997) Nature 385:544- 548; Hemmings (1997) Science 275:628-630; Dudek et al. (1997) Science, 275:661-665).
  • PI3K platelet derived growth factor
  • NGF nerve growth factor
  • IGF-1 insulin like growth factor 1
  • PI3K or dominant negative Akt mutants abolish survival promoting activities of these growth factors or cytokines. It has been previously disclosed that inhibitors of PI3K (LY294002 or wortmannin) blocked the activation of Akt by upstream kinases. In addition, introduction of constitutively active PI3K or Akt mutants promotes cell survival under conditions in which cells normally undergo apoptotic cell death (Kulik et al. (1997); Dudek et al. (1997)). These and other observations suggest that the PI3K/Akt pathway plays an important role in regulating cell survival or apoptosis in tumorigenesis. See WO 2008/070016.
  • PI3K/AKT pathway inhibitors have been proposed as therapeutic agents for the treatment of cancer, but their use has been hampered by dose-limiting skin rash. See, e.g., Tolcher et al. (2009) J. Clin. Oncol. 27: 15s (abstract 3503) (MK-2206, Merck); Edelman et al. (2010) J. Clin. Oncol. 28: 15s (abstract 3004) (XL147/SAR245408, Exilixis, sanofi- aventis, Merck KGaA) and Baselga et al. (2010) J. Clin. Oncol. 28:15s (abstract 3003) (BKM120, Novartis).
  • cancer treatment is directed to blocking signaling via the PI3K/AKT pathway.
  • the cancer treatment blocks signaling via the PI3K/AKT pathway by blocking the activity of epidermal growth factor receptor (EGFR), PI3K, AKT and/or mTor.
  • EGFR epidermal growth factor receptor
  • the cancer therapy involves blocking the activity of AKT.
  • the cancer treatment involves blocking signaling via the PI3K/AKT pathway using a chemical compound, such as a chemical compound that blocks the activity of EGF/EGFR, PI3K, AKT and/or mTor.
  • the chemical compound blocks the activity of AKT.
  • the side effect is skin rash.
  • the method or agent for treating and/or preventing side effects of treatment with PI3K/AKT pathway inhibitors, such as cancer treatment is a method or agent for antagonizing the activity of interleukin-23 (IL-23).
  • the method or agent for treating and/or preventing side effects of treatment with PI3K/AKT pathway inhibitors, such as cancer treatment is a chemical compound that antagonizes the activity of IL-23, referred to herein as an IL-23 antagonist.
  • the IL-23 antagonist is an agent that specifically binds to the pl9 subunit of IL-23, or that specifically binds to the IL-23R subunit of the IL-23 receptor complex.
  • the IL-23 antagonist is an antibody, or antigen binding fragment thereof, that binds to IL-23, including but not limited to an antibody, or antigen binding fragment thereof, that specifically binds to the pl9 subunit of IL-23.
  • the invention provides methods of treatment comprising determining whether a subject is suffering from a skin rash that may be due to administration of a PI3K/AKT pathway inhibitor, and administering an effective amount of an IL-23 antagonist to treat the rash only if such rash is present.
  • the invention provides methods of treatment comprising administering an IL-23 antagonist to a subject to be treated with a PI3K/AKT pathway inhibitor specifically for the purpose of preventing or treating a skin rash, and thereafter optionally monitoring the subject's skin for signs and symptoms of a skin rash.
  • the PI3K/AKT pathway inhibitor is an AKT inhibitor, such as a substituted naphthyridine compound, including MK-2206 and AKTi-X.
  • the AKT inhibitor is perifosine (KRX-0401), VQD-002 (API-2, TCN), SR13668, GSK690693, GSK2110183, GSK2141795, AZD5363 or XL418.
  • the AKT inhibitor is dosed orally.
  • the AKT inhibitor is dosed in combination with one or more other cancer drugs, e.g. a MEK inhibitor such as selumetinib or GSKl 120212.
  • treatment with an IL-23 antagonist permits dosing with AKT inhibitors at levels that might otherwise be difficult or impossible to achieve due to dose limiting skin rash, such as weekly dosing of 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10,000 mg or more, either as a single agent or in combination with another cancer drug or drugs.
  • the dosing interval differs from once every week, such as TID, BID, daily, Q2D, Q3D, Q4D, Q5D, Q6D, Q2W, Q3W, Q4W, but nonetheless results in a total weekly dose of 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10,000 mg or more.
  • the AKT inhibitor is dosed to a human subject at 150 - 500 mg once every week, such as 300 mg once every week, or at 45 - 150 mg every other day.
  • the AKT inhibitor is dosed to a human subject as part of combination therapy at 150 - 500 mg once every week, such as 300 mg once every week, or at 150 - 500 mg once every three weeks.
  • the PI3K/AKT pathway inhibitor is a PI3K inhibitor, such as wortmannin, LY294002, BEZ235, BGT226, BKM120, XL765, XL147, GDC0941, SF1126, GSK1059615, PX-866 or CAL-101.
  • the PI3K/AKT pathway inhibitor is an EGF/EGFR inhibitor, such as cetuximab, gefitnib, erlotinib or panitumumab.
  • the anti-IL-23 antibody, or antigen binding fragment thereof comprises an antibody light chain variable domain, or antigen binding fragment thereof, having at least one, two or three CDRs selected from the group consisting of SEQ ID NOs: 32-46.
  • antibody or fragment comprises a light chain variable domain comprising at least one CDRLl selected from the group consisting of SEQ ID NOs: 32-36; at least one CDRL2 selected from the group consisting of SEQ ID NOs: 37-41; and at least one CDRL3 selected from the group consisting of SEQ ID NOs: 42-46.
  • the anti-IL-23 antibody, or antigen binding fragment thereof comprises an antibody heavy chain variable domain, or antigen binding fragment thereof, having at least one, two or three CDRs selected from the group consisting of SEQ ID NOs: 15-31.
  • the antibody or fragment comprises a heavy chain variable domain comprising at least one CDRH1 selected from the group consisting of SEQ ID NOs: 15-19; at least one CDRH2 selected from the group consisting of SEQ ID NOs: 20-26; and at least one CDRH3 selected from the group consisting of SEQ ID NOs: 27-31.
  • the antibody or fragment comprises a light chain variable domain and a heavy chain variable domain, or the antigen binding fragments thereof, described in the preceding two paragraphs.
  • the antibody or fragment comprises a framework region, wherein the amino acid sequence of the framework region is all or substantially all of the corresponding region of a human immunoglobulin amino acid sequence.
  • the light chain and/or heavy chain variable domains comprise a variant of one or more of the CDRs.
  • the variant domain comprises up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more conservatively modified amino acid residues relative to the sequence of the respective SEQ ID NOs. Conservative amino acid substitutions are provided at Table 1.
  • the light chain variable domain comprises residues 1-
  • the heavy chain variable domain comprises a sequence selected from the group consisting of residues 1-116 of SEQ ID NOs: 6-8, such as SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8.
  • the variant variable domain comprises up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40 or 50 or more conservatively modified amino acid residues relative to the sequence of the respective SEQ ID NOs.
  • the antibody or fragment comprises a light chain variable domain and a heavy chain variable domain, or the antigen binding fragments thereof, described in this paragraph.
  • the antibody or fragment comprises a light chain sequence of SEQ ID NO: 14 and/or a heavy chain sequence selected from the group consisting of SEQ ID NOs: 6-8. In another embodiment the antibody or fragment comprises two light chain sequences and two heavy chain sequences.
  • the antibody or fragment comprises a light chain variable domain, or an antigen binding fragment thereof, consisting essentially of residues 1- 108 of SEQ ID NO: 14, and/or a heavy chain variable domain, or an antigen binding fragment thereof, consisting essentially of a sequence selected from the group consisting of residues 1- 116 of SEQ ID NOs: 6-8, such as SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8.
  • the antibody or fragment comprises a light chain variable domain, or an antigen binding fragment thereof, having at least 50%, 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence homology with residues 1-108 of SEQ ID NO: 14, and/or a heavy chain variable domain, or an antigen binding fragment thereof, having at least 50%, 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence homology with a sequence selected from the group consisting of residues 1-116 of SEQ ID NOs: 6-8, such as SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO: 8.
  • the antibody or fragment binds to human IL-23pl9 (SEQ ID NO: 1]
  • the IL-23pl9 binding compound binds to an epitope comprising some or all of residues K20, T23, W26, S27, P30, E82, S95, L96, L97, P98, D99, P101, G103, Q104, H106, A107 and LI 10, and optionally residues L24, L85, T91, S100 and V102.
  • the epitope for an antibody of interest is determined by obtaining an X-ray crystal structure of an antibody: antigen complex and determining which residues on IL-23pl9 are within a specified distance of residues on the antibody of interest, wherein the specified distance is, e.g., 4A or 5A.
  • the epitope is defined as a stretch of 11 or more contiguous amino acid residues along the IL-23 l9 sequence in which at least 30%, 40%, 45%), 50%o or 54% of the residues are within the specified distance of the antibody.
  • the anti-IL-23 antibodies or fragments are able to block the binding of a binding compound of the present invention to human IL-23 in a cross- blocking assay.
  • the anti-IL-23 antibodies or fragments are able to block IL-23 -mediated activity, such activities including but not limited to, binding to its receptor and promoting the proliferation or survival of T R 17 cells.
  • the antibody or fragment further comprises a heavy chain constant region, wherein the heavy chain constant region comprises a ⁇ , ⁇ 2, ⁇ 3, or ⁇ 4 human heavy chain constant region, or a variant thereof.
  • the light chain constant region comprises a lambda or a kappa human light chain constant region, or a variant thereof.
  • the anti-IL-23 antibodies or fragments thereof are polyclonal, monoclonal, chimeric, humanized or fully human antibodies or fragments thereof.
  • the present invention also contemplates that the antigen binding fragment is an antibody fragment selected from the group consisting of, e.g., Fab, Fab', Fab'-SH, Fv, scFv, F(ab') 2 , and a diabody.
  • FIG. 1 shows comparisons of mouse anti-human IL-23pl9 antibody clone heavy chain variable domain sequences. Sequences are provided for clones mlAl 1, ml 1C1, m5F5, m21Dl, ml3B8, hl3B8a, hl3B8b and hl3B8c. CDRs are indicated. In both figures, an "m” prefix connotes a murine antibody and an "h” connotes a humanized antibody. The suffixes "a”, “b” and “c” refer to sequence variants of the humanized 13B8 heavy chain variable domain, as discussed in greater detail below.
  • FIG. 2 shows comparisons of mouse anti-human IL-23pl9 antibody clone light chain variable domain sequences. Sequence are provided for clones mlAl 1, ml 1C1, m5F5, m21Dl, ml3B8, hl3B8. CDRs are indicated.
  • FIG. 3 shows the levels of expression of the genes encoding the subunits of IL-
  • the leftmost (white) bar in each graph which is essentially zero for the IL-23 l9 and IL-12/23p40 plots, represents control cells treated with vehicle.
  • the next (black) bar represents cells treated with lipopolysaccharide (LPS).
  • the next two bars represent cells treated with LPS and MK-2206 (0.1 ⁇ and 0.5 ⁇ , respectively), as indicated.
  • the right most two bars represent cells treated with LPS and AKTi-X (0.1 ⁇ and 0.5 ⁇ , respectively, as indicated).
  • LPS enhances the expression of IL-23pl9 and IL-12/23p40, but reduces the expression of IL-12p35.
  • AKT inhibitors MK- 2206 and AKTi-X both further enhance expression of IL-23pl9 and IL-12/23p40, but enhance the expression of IL-12p35 less so, if at all.
  • the results demonstrate that in the presence of LPS, AKT inhibitors preferentially enhance the expression of the genes encoding the subunits of IL-23 rather than IL-12. See Example 3.
  • FIG. 4 shows the levels of expression of the genes encoding the pl9 and p40 subunits of IL-23 in primary CD 14+ monocytes isolated from PBMC from two different human donors as determined by TAQMAN ® real time quantitative polymerase chain reaction analysis. Data are presented for three time points (3, 6 and 24 hours) after addition of LPS, or LPS and AKT inhibitor AKTi-X, as indicated. Bars for untreated cells (indicated by arrows) are provided with the three hour time points, and are essentially zero. For each time point, the left (black) bars are data for treatment with LPS alone, and the right (white) bars are data for treatment with LPS and AKT inhibitor AKTi-X.
  • AKTi-X an AKT inhibitor specifically upregulates expression of genes encoding IL-23 subunits in primary CD 14+ monocytes isolated from PBMC.
  • IL- 12p35 is not expressed at detectable levels at three and six hours, and is expressed at only low levels at 24 hours and does not change with addition of AKT inhibitor AKTi-X (data not shown). See Example 4.
  • FIG. 5 shows IL-23 protein levels in primary CD 14+ monocytes isolated from
  • TLR toll-like receptor
  • LTA lipoteichoic acid
  • AKT inhibitors MK-2206 or AKTi-X at 0.1 ⁇ or 0.5 ⁇ .
  • the leftmost bars for vehicle controls are not visible. Black bars show results for treatment with TLR agonist alone; white bars for treatment with TLR agonist and MK-2206 (at 0.1 ⁇ or 0.5 ⁇ ); and gray bars for treatment with TLR agonist and AKTi-X (at 0.1 ⁇ or 0.5 ⁇ ), as indicated.
  • FIGS. 6A and 6B compare expression of several genes in IL-23-treated and
  • MK-2206-treated monkeys Specifically, gene expression levels are compared between IL- 23-treated cynomolgus monkey skin (black symbols, top panels) and MK-2206-treated rhesus monkey skin (black symbols, bottom panels), as well an (untreated) controls (gray symbols).
  • Each of the genes for which data are presented (BD2, S100A8-calgranulin, CCL3-MIPl , Ebi3, IL- ⁇ , IL-6, IL-23pl9, IL-22) was selected based on its prior known association with IL-23 -induced skin inflammation. Both IL-23 and AKT inhibitor increase the expression of each gene shown. See Example 6.
  • PI3K refers to PI3 kinase.
  • PI3 kinase/AKT pathway inhibitor or " PI3K/AKT pathway inhibitor” refers to any agent that inhibits signaling via the PI3 kinase/AKT pathway, including but not limited to inhibitors of PI3 kinase and inhibitors of AKT. It also includes compounds that act "upstream" of PI3K in the PI3 kinase/AKT pathway, such as epidermal growth factor or its receptor (EGF/EGFR), since such compounds can inhibit signaling via the PI3 kinase/AKT pathway by removing an upstream triggering signal.
  • EGF/EGFR epidermal growth factor or its receptor
  • PI3 kinase/AKT pathway inhibitors encompass inhibitors of any activity that signals through or within the PI3 kinase/AKT pathway since any of these inhibitors may give rise to a rash that can benefit from the methods of the present invention.
  • AKTi refers to an AKT inhibitor generally.
  • AKTi-X refers to a specific PI3 kinase/AKT pathway inhibitor.
  • AKT inhibitor tra/75-3-amino-3- ⁇ 4-[l-(difluoromethyl)-8-phenyl[ 1,2,4] triazolo[4,3-a]-l,5- naphthyridin-7-yl]lphenyl ⁇ -l-methylcyclobutanol), as described herein.
  • MK-2206 refers to a specific AKT inhibitor, 8-[4-(l-aminocyclobutyl)phenyl]-9-phenyl[l,2,4]triazolo[3,4-f]-l,6- naphthyridin-3(2H)-one, as described herein.
  • AKT is also known as protein kinase B (PKB).
  • IL-23 antagonist refers to any agent that inhibits signaling by IL-23.
  • antagonists of the IL-23 receptor complex are also IL-23 antagonists.
  • a "non-specific IL-23 antagonist” is an agent that blocks the activity of both IL-23 and IL-12.
  • An "IL-23 -specific antagonist” is an agent that selectively blocks the activity of IL-23 but does not block the activity of IL-12.
  • IL-23 and “IL-12” as used herein refer to human IL-23 and human IL-12. The antibodies disclosed herein bind to human IL-23.
  • Proliferative activity encompasses an activity that promotes, that is necessary for, or that is specifically associated with, e.g., normal cell division, as well as cancer, tumors, dysplasia, cell transformation, metastasis, and angiogenesis.
  • administering refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • administering can refer, e.g., to therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • administering also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding composition, or by another cell.
  • Treatment refers to therapeutic treatment, prophylactic or preventative measures, to research and diagnostic applications.
  • Treatment as it applies to a human, veterinary, or research subject, or cell, tissue, or organ, encompasses contact of an agent with animal subject, a cell, tissue, physiological compartment, or physiological fluid.
  • “Treatment of a cell” also encompasses situations where the agent contacts IL-23 receptor (IL-23R/IL-12Rpi heterodimer), e.g., in the fluid phase or colloidal phase, but also situations where the agonist or antagonist does not contact the cell or the receptor.
  • the term "antibody” refers to any form of antibody that exhibits the desired biological activity. Thus, it is used in the broadest sense and specifically covers monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), chimeric antibodies, humanized antibodies, fully human antibodies, etc. so long as they exhibit the desired biological activity.
  • an antibody or fragment is an antibody or fragment that specifically binds to IL-23.
  • IL-23 binding fragment As used herein, the terms “IL-23 binding fragment,” “binding fragment thereof,” “antigen binding fragment thereof or “fragment” (when used with reference to an antibody) encompass a fragment or a derivative of an antibody that still substantially retains its biological activity of inhibiting IL-23pl9 activity. Therefore, the term “antibody fragment” or “IL-23 binding fragment” refers to a portion of a full length antibody, generally the antigen binding or variable region thereof. Examples of antibody fragments include Fab, Fab', F(ab') 2 , and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., sc-Fv; and multispecific antibodies formed from antibody fragments.
  • a binding fragment or derivative retains at least 10% of its IL-23 inhibitory activity.
  • a binding fragment or derivative retains at least 25%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or 100% (or more) of its IL-23 inhibitory activity, although any binding fragment with sufficient affinity to exert the desired biological effect will be useful.
  • an IL-23 binding fragment can include variants having conservative amino acid substitutions that do not substantially alter its biologic activity.
  • the term "monoclonal antibody,” as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of antibodies directed against (or specific for) different epitopes. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • the "monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581- 597, for example.
  • Antibodies, and antigen binding fragments thereof may be described herein as comprising a light and/or heavy chain variable domain, or as comprising a light and/or heavy chain. As used herein, and consistent with their plain meanings, such descriptions encompass embodiments in which the antibody, or antigen binding fragment thereof, includes more than one light and/or heavy chain variable domain and/or chain, such as two light and/or heavy chain variable domains and/or chains.
  • the monoclonal antibodies herein specifically include “chimeric” antibodies
  • immunoglobulins in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
  • a “domain antibody” is an immunologically functional immunoglobulin fragment containing only the variable region of a heavy chain or the variable region of a light chain.
  • two or more V H regions are covalently joined with a peptide linker to create a bivalent domain antibody.
  • the two V H regions of a bivalent domain antibody may target the same or different antigens.
  • a “bivalent antibody” comprises two antigen binding sites. In some instances, the two binding sites have the same antigen specificities. However, bivalent antibodies may be bispecific (see below).
  • single-chain Fv or "scFv” antibody refers to antibody fragments comprising the V H and V L domains of antibody, wherein these domains are present in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the sFv to form the desired structure for antigen binding.
  • the monoclonal antibodies herein also include camelized single domain antibodies. See, e.g., Muyldermans et al. (2001) Trends Biochem. Sci. 26:230; Reichmann et al. (1999) J. Immunol. Methods 231 :25; WO 94/04678; WO 94/25591; U.S. Pat. No.
  • the present invention provides single domain antibodies comprising two V H domains with modifications such that single domain antibodies are formed.
  • diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy chain variable domain (V H ) connected to a light chain variable domain (V L ) in the same polypeptide chain (V H -V L or V L - V H ).
  • V H heavy chain variable domain
  • V L light chain variable domain
  • the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.
  • Diabodies are described more fully in, e.g., EP 404,097; WO 93/11161; and Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448. For a review of engineered antibody variants generally see Holliger and Hudson (2005) Nat.
  • humanized antibody refers to forms of antibodies that contain sequences from non-human ⁇ e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • the humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions may be included to increase affinity, increase stability of the humanized antibody, or for other reasons. [0049]
  • the antibodies of the present invention also include antibodies with modified
  • Alterations of the Fc region include amino acid changes (substitutions, deletions and insertions), glycosylation or deglycosylation, and adding multiple Fc. Changes to the Fc can also alter the half-life of antibodies in therapeutic antibodies, and a longer half-life would result in less frequent dosing, with the concomitant increased convenience and decreased use of material. See Presta (2005) J. Allergy Clin. Immunol.116:731 at 734-35.
  • Fully human antibody refers to an antibody that comprises human immunoglobulin protein sequences only.
  • a fully human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell.
  • mouse antibody refers to an antibody which comprises mouse immunoglobulin sequences only.
  • a fully human antibody may be generated in a human being, in a transgenic animal having human immunoglobulin germline sequences, by phage display or other molecular biological methods.
  • hypervariable region refers to the amino acid residues of an antibody that are responsible for antigen-binding.
  • the hypervariable region comprises amino acid residues from a "complementarity determining region” or "CDR" ⁇ e.g. residues 24-34 (CDRL1), 50-56 (CDRL2) and 89-97 (CDRL3) in the light chain variable domain and residues 31-35 (CDRH1), 50-65 (CDRH2) and 95-102 (CDRH3) in the heavy chain variable domain (Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed.
  • CDR complementarity determining region
  • Binding compound refers to a molecule, small molecule, macromolecule, polypeptide, antibody or fragment or analogue thereof, or soluble receptor, capable of binding to a target.
  • Binding compound also may refer to a complex of molecules, e.g., a non- covalent complex, to an ionized molecule, and to a covalently or non-covalently modified molecule, e.g., modified by phosphorylation, acylation, cross-linking, cyclization, or limited cleavage, which is capable of binding to a target.
  • binding compound refers to both antibodies and antigen binding fragments thereof.
  • Binding refers to an association of the binding composition with a target where the association results in reduction in the normal Brownian motion of the binding composition, in cases where the binding composition can be dissolved or suspended in solution.
  • Binding composition refers to a molecule, e.g. a binding compound, in combination with a stabilizer, excipient, salt, buffer, solvent, or additive, capable of binding to a target.
  • Constantly modified variants or “conservative substitution” refers to substitutions of amino acids that may be made, as known by those of skill in the art, with little or no impact on the biological activity of the resulting molecule, even in essential regions of the polypeptide. Such exemplary substitutions are preferably made in accordance with those set forth in Table 1 as follows:
  • a binding compound that consists essentially of a recited amino acid sequence may also include one or more amino acids, including substitutions of one or more amino acid residues, that do not materially affect the properties of the binding compound.
  • Effective amount encompasses an amount sufficient to ameliorate or prevent a symptom or sign of the medical condition. Effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • An effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the overall health of the patient, the method route and dose of administration and the severity of side affects. See, e.g., U.S. Pat. No. 5,888,530.
  • An effective amount can be the maximal dose or dosing protocol that avoids significant side effects or toxic effects.
  • the effect will result in an improvement of a diagnostic measure or parameter by at least 5%, usually by at least 10%, more usually at least 20%, most usually at least 30%>, preferably at least 40%>, more preferably at least 50%, most preferably at least 60%, ideally at least 70%, more ideally at least 80%>, and most ideally at least 90%>, where 100%) is defined as the diagnostic parameter shown by a normal subject. See, e.g., Maynard et al. (1996) A Handbook of SOPs or Good Clinical Practice, Interpharm Press, Boca Raton, FL; Dent (2001) Good Laboratory and Good Clinical Practice, Urch Publ., London, UK.
  • the expressions "cell,” “cell line,” and “cell culture” are used interchangeably and all such designations include progeny.
  • the words “transformants” and “transformed cells” include the primary subject cell and cultures derived therefrom without regard for the number of transfers. It is also understood that all progeny may not be precisely identical in DNA content, due to deliberate or inadvertent mutations. Mutant progeny that have the same function or biological activity as screened for in the originally transformed cell are included. Where distinct designations are intended, it will be clear from the context.
  • samples or assays comprising a given, e.g., protein, gene, cell, or organism, are treated with a potential activating or inhibiting agent and are compared to control samples without the agent.
  • Control samples i.e., not treated with agent, are assigned a relative activity value of 100%.
  • Inhibition is achieved when the activity value relative to the control is about 90%> or less, typically 85% or less, more typically 80%> or less, most typically 75% or less, generally 70%> or less, more generally 65%> or less, most generally 60%> or less, typically 55% or less, usually 50% or less, more usually 45% or less, most usually 40% or less, preferably 35% or less, more preferably 30%) or less, still more preferably 25% or less, and most preferably less than 25%.
  • Activation is achieved when the activity value relative to the control is about 110%, generally at least 120%, more generally at least 140%, more generally at least 160%, often at least 180%, more often at least 2-fold, most often at least 2.5-fold, usually at least 5-fold, more usually at least 10-fold, preferably at least 20-fold, more preferably at least 40-fold, and most preferably over 40-fold higher.
  • Endpoints in activation or inhibition can be monitored as follows. Activation, inhibition, and response to treatment, e.g., of a cell, physiological fluid, tissue, organ, and animal or human subject, can be monitored by an endpoint.
  • the endpoint may comprise a predetermined quantity or percentage of, e.g., an indicia of inflammation, oncogenicity, or cell degranulation or secretion, such as the release of a cytokine, toxic oxygen, or a protease.
  • the endpoint may comprise, e.g., a predetermined quantity of ion flux or transport; cell migration; cell adhesion; cell proliferation; potential for metastasis; cell differentiation; and change in phenotype, e.g., change in expression of gene relating to inflammation, apoptosis, transformation, cell cycle, or metastasis (see, e.g., Knight (2000) Ann. Clin. Lab. Sci. 30: 145- 158; Hood and Cheresh (2002) Nature Rev. Cancer 2:91-100; Timme et al. (2003) Curr. Drug Targets 4:251-261; Robbins and ltzkowitz (2002) Med. Clin. North Am. 86: 1467-1495; Grady and Markowitz (2002) Annu. Rev. Genomics Hum. Genet. 3:101-128; Bauer, et al. (2001) Glia 36:235-243; Stanimirovic and Satoh (2000) Brain Pathol. 10:113-126).
  • An endpoint of inhibition is generally 75% of the control or less, preferably
  • an endpoint of activation is at least 150% the control, preferably at least two times the control, more preferably at least four times the control, and most preferably at least 10 times the control.
  • a specified ligand binds to a particular receptor and does not bind in a significant amount to other proteins present in the sample.
  • an antibody is said to bind specifically to a polypeptide comprising a given sequence (in this case IL-23pl9) if it binds to polypeptides comprising the sequence of IL-23pl9 but does not bind to proteins lacking the sequence of IL-23pl9.
  • an antibody that specifically binds to a polypeptide comprising IL-23pl9 may bind to a FLAG ® -tagged form of IL-23pl9 but will not bind to other FLAG ® -tagged proteins.
  • the antibody, or binding composition derived from the antigen-binding site of an antibody, of the contemplated method binds to its antigen with an affinity that is at least two fold greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with unrelated antigens.
  • the antibody will have an affinity that is greater than about 10 9 liters/mol, as determined, e.g., by Scatchard analysis. Munsen et al. (1980) Analyt. Biochem. 107:220-239.
  • the PI3K/AKT signaling pathway is the most frequently hyperactivated pathway in cancer. Inhibition of PI3K/AKT pathway is expected to have a significant impact on cancer cell survival and proliferation.
  • drugs targeting this pathway are currently in clinical trials (Liu et a/.(2009) Nat. Rev. Drug Disc. 8:627) including MK-2206, an allosteric inhibitor of AKT. Maculopapular skin rash is the dose limiting toxicity for MK-2206 in the clinic. Tolcher et a/. (2009) J. Clin. Oncol. 27:15s (abstract 3503).
  • the rash appears 7-10 days after the first dose and resolves completely after discontinuation of treatment with the drug. Skin rash is most prevalent at doses above 60 mg QOD, such as 75 mg and 90 mg (and presumably higher doses as well).
  • the present invention relates to the discovery that IL-23 is involved in skin rash that results from treatment with PI3K/AKT pathway inhibitors, e.g. for treatment of cancer.
  • This skin rash has been a dose-limiting toxicity for the AKT inhibitor MK-2206 in the clinic.
  • the invention involves antagonism of IL-23, such as treatment with an IL-23 antagonist, to ameliorate this rash. Elimination or reduction of the rash will have value as a matter of comfort to the patient, and may improve compliance. In addition, elimination or reduction of the rash may allow for elevated dosing and concomitant increased anti-tumor efficacy.
  • the present invention is based in part of studies of this MK-2206-induced skin rash.
  • Pathological examination of skin rash biopsies reveals marked perivascular infiltrates with T cells and abundant macrophages.
  • psoriasiform dermatitis is observed with epidermal hyperplasia and increased keratinocyte proliferation.
  • Other investigational drugs targeting the PI3K/AKT pathway have similar side effects ⁇ e.g., Edelman et al. (2010) J. Clin. Oncol. 28:15s (abstract 3004) and Baselga et al. (2010) J. Clin. Oncol. 28: 15s (abstract 3003)), suggesting that skin rashes are mechanism-based.
  • TLR agonists were included in these experiments based on the hypothesis that AKT inhibitor-induced skin rash is TLR dependent, and thus that TLR agonists should be present in culture to mimic the presence of microbial TLR agonists on natural skin. As illustrated in FIGS. 3 and 4, inhibition of AKT results in significant increase in IL-23 subunit mRNA.
  • FIG. 5 shows AKT inhibitor-induced elevation of IL-23 at the protein level as well.
  • Similarities include similar morphology (perivascular dermal infiltrate with T cell and macrophage components); abnormal stratum corneum, including occasional neutrophilic abscesses, loss of "basket weave” appearance, and abnormal filaggrin staining; epidermal hyperplasia; and increased basal keratinocyte proliferation. Both human and rhesus monkey rashes involve T cell and macrophage infiltrates, and both involve
  • TAQMAN ® real time quantitative polymerase chain reaction analysis was also performed on skin derived from MK-2206- and IL-23-treated monkeys.
  • 32 genes were selected for measurement based on their previous association with IL-23 -induced skin inflammation, as well as eight other genes of interest (VEGFA, CD4, CD8a, CD68, IL-10, TLR2, TLR4, VEGFR1).
  • Exemplary results are provided in Table 2 for two control rhesus monkeys and one MK-2206- treated rhesus monkey. Data are presented for two or three distinct skin samples obtained from each monkey. Values in bold- face are elevated at least two-fold higher than control levels,. As used herein, these two-fold changes constitute upregulation of gene expression. Of the 32 genes previously associated with IL-23-induced skin inflammation, seven were not detected in the monkey samples (IL-24, IL-17A, GM-CSF, IL-12p40, IL-23R, RANKL, IL- 26).
  • Control Rhesus 1 Control Rhesus 2 MK-2206-treated Rhesus
  • CD4 14.0 18.4 16.0 9.8 12.5 12.5 8.9
  • VEGFR1 13.9 11.3 11.6 8.7 8.9 7.0 8.3
  • FIGS. 6 A and 6B also provide exemplary gene expression data for
  • AKT inhibitor-induced rash AKT inhibitors induce IL-23 subunit gene expression and increase IL-23 levels in cells in vitro.
  • MK-2206 also induces a rash in monkeys that is histologically very similar to the clinically observed MK-2206-induced rash in human subjects, and is also very similar to skin inflammation induced by injection of IL-23 into monkey skin.
  • Many of the same genes induced by injection of IL-23 into primate skin are also induced in the primate model of MK-2206-induced rash, effectively mimicking the "gene expression profile" of IL-23 skin inflammation.
  • IL-23 appears to be involved in mediating AKT inhibitor-induced skin rash
  • inhibition of IL-23 -induced skin inflammation is promising approach to prevent and/or treat this rash.
  • Such treatment may eliminate the dose limiting toxicity of PI3K/AKT pathway inhibitors, such as MK-2206, and permit higher and potentially more efficacious dosing, e.g. for the treatment of cancer.
  • This potential increase in the therapeutic window for PI3K/AKT pathway inhibitors may allow for effective treatment with compounds that would otherwise face dose-limiting toxicity (rash) that limited their effectiveness.
  • Antagonism of IL-23 may also find use in treatment of rashes caused by other drugs that disrupt signaling via the PI3K/AKT pathway.
  • Epidermal grown factor (EGF) signals via the epidermal grown factor receptor (EGFR), which is overexpressed in many tumors. EGRF then acts, at least in part, via the PI3K/AKT pathway.
  • EGF/EGFR signaling have been proposed for the treatment of cancer, e.g. cetuximab
  • PI3K/AKT pathway Other receptors that signal via the PI3K/AKT pathway include human epidermal growth factor receptor 2 (HER2/neu, ErbB-2), hepatocyte growth factor receptor (HGFR, MET) and other receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). Inhibitors of signaling through these receptors may also induce the same rash that is observed with PI3K and AKT inhibitors, and thus may similarly benefit from the methods of the present invention.
  • HER2/neu, ErbB-2 human epidermal growth factor receptor 2
  • HGFR hepatocyte growth factor receptor
  • RTKs receptor tyrosine kinases
  • GPCRs G protein-coupled receptors
  • IL-23 has been show to promote tumor incidence and growth an animal models (Langowski et al. (2006) Nature 442:461) and antagonism of IL-23 has been proposed as a method to inhibit tumor growth (US 7,282,204). This advantage is not shared by antagonists of both IL-23 and IL-12, such as anti-p40 antibodies like ustekinumab and briakinumab. See Langowski et al. (2006) Nature 442:461 at Figs. 4(a), (f) and (g).
  • IL-23 Specific inhibition of IL-23 (but not IL-12) should also reduce the risk of various infections that would otherwise be elevated by an IL- 12/IL-23 antagonist, such as an anti-p40 antibody. Bowman et al. (2006) Curr. Op. Infect. Dis. 19:245. The reduced tumor and infection risks will be of great benefit to cancer patients being treated for PI3K/AKT pathway inhibitor-induced skin rash by the methods of the present invention involving IL-23 -specific antagonists.
  • the present invention involves antagonism of IL-23 activity as a means of ameliorating skin rash associated with cancer therapy using PI3K/AKT pathway inhibitors.
  • the method may be of use in treating a skin rash resulting from treatment with any
  • the AKT inhibitor of the present invention is a substituted naphthyridine compound, for example as disclosed in WO 2008/070016 (to Merck & Co., Inc. and Banyu Pharmaceutical Co., Ltd.).
  • the AKT inhibitor is 8- [4-( 1 -aminocyclobutyl)phenyl] -9-phenyl[ 1 ,2,4]triazolo [3 ,4-f] - 1 ,6-naphthyridin-3 (2H)-one (MK-2206) or a pharmaceutically acceptable salt thereof, as disclosed and claimed at US 7,576,209. See also WO 2008/070041 (to Merck & Co., Inc.), which is hereby incorporated by reference in its entirety.
  • the AKT inhibitor is a substituted [l,2,4]triazolo[4,3-a]-
  • 1,5 -naphthyridine compound e.g. tra/?5-3-amino-3- ⁇ 4-[l-(difluoromethyl)-8-phenyl[ 1,2,4] triazolo[4,3-a]-l,5-naphthyridin-7-yl]lphenyl ⁇ -l-methylcyclobutanol
  • AKTi-X alpha-1-naphthyridine compound, e.g. tra/?5-3-amino-3- ⁇ 4-[l-(difluoromethyl)-8-phenyl[ 1,2,4] triazolo[4,3-a]-l,5-naphthyridin-7-yl]lphenyl ⁇ -l-methylcyclobutanol
  • Additional exemplary AKT inhibitors include, but are not limited to: 1 - ⁇ 4-[3-(l -methyl-lH-imidazol-4-yl)-9-phenyl[ 1 ,2,4]triazolo[3,4- J-l ,6-naphthyridin-8- yl]phenyl ⁇ cyclobutanamine;
  • a reaction scheme for the production of exemplary AKT inhibitors of the present invention is provided at Example 2.
  • the AKT inhibitor of the present invention is an AKT allosteric inhibitor selected from among the compounds disclosed in WO 2005/100344;
  • the AKT inhibitor of the present invention is selected from among the compounds disclosed in US 2008/076763 (to Glaxo SmithKline LLC);
  • the AKT inhibitor is perifosine (KRX-0401) (Keryx); VQD-002 (API-2, TCN) (VioQuest); SR13668 (SRI
  • the AKT inhibitor is dosed in combination with one or more other cancer drugs.
  • the other cancer drug is a MEK inhibitor such as AZD6244 (selumetinib/ARRY-886)(AstraZeneca) or GSK1120212
  • the PI3K/AKT pathway inhibitors of the present invention may be administered to mammals, including humans, either alone or, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the inhibitors (compounds) can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbito
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p- hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p- hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p- hydroxybenzoate
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha- tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • compositions may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
  • the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of Formula A may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary
  • Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula A are employed.
  • topical application shall include mouth washes and gargles.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • composition according to this invention When a composition according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • the dosage regimen utilizing the compounds of the instant invention can be selected in accordance with a variety of factors including type, species, age, weight, sex and the type of cancer being treated; the severity (i.e., stage) of the cancer to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to treat, for example, to prevent, inhibit (fully or partially) or arrest the progress of the disease.
  • compounds of the instant invention can be administered in a total daily dose of up to 10,000 mg.
  • Compounds of the instant invention can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), and three times daily (TID).
  • Compounds of the instant invention can be administered at a total daily or weekly dosage of up to 10,000 mg, e.g., 2,000 mg, 3,000 mg, 4,000 mg, 6,000 mg, 8,000 mg or 10,000 mg, which can be administered in one daily dose or can be divided into multiple daily doses as described above.
  • compounds of the instant invention can be administered in a total daily dose of up to 1 ,000 mg.
  • Compounds of the instant invention can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), and three times daily (TID).
  • compounds of the instant invention can be administered less frequently, such as once a day (QD), once every other day (QOD), once every week (QW), or once every other week (QOW).
  • Compounds of the instant invention can be administered at a total daily or weekly dosage of up to 1,000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800 mg or 1 ,000 mg, which can be administered in one daily dose or can be divided into multiple daily doses as described above.
  • the administration can be continuous, i.e., every day, or intermittently.
  • intermittent administration of a compound of the instant invention may be administration one to six days per week or it may mean administration in cycles (e.g. daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) or it may mean administration on alternate days.
  • the compounds of the instant invention may be administered according to any of the schedules described above, consecutively for a few weeks, followed by a rest period.
  • the compounds of the instant invention may be administered according to any one of the schedules described above from two to eight weeks, followed by a rest period of one week, or twice daily at a dose of 100 - 500 mg for three to five days a week.
  • the compounds of the instant invention may be
  • Preparations of the monohydrochloride salt of MK-2206 may be prepared as a tablet involving roller compression granulation followed by milling, mixing with the other inactive ingredients, compression, and film coating.
  • Some of the diluents or fillers for use in this formulation are preferably swellable agents, and may include, but are not limited to, various grades of microcrystallme cellulose, such as Avicel PH101, Avicel PH102, & Avicel PH200. If microcrystallme cellulose is added, it is preferably from about 50 to 180 microns in size, more preferably about 100.
  • Avicel PH 101 has a mean particle size of about 50
  • Avicel PH 102 has a mean particle size of about 100
  • Avicel PH 200 has a mean particle size of about 190 microns.
  • the preferred microcrystallme cellulose is Avicel PH 102.
  • the edible calcium salts suitable for use herein include but are not limited to, dibasic calcium phosphate dihydrate, calcium phosphate anhydrous, and tribasic calcium phosphate; or mixtures thereof.
  • a preferred edible calcium salt is the dibasic calcium phosphate anhydrous, which also provides good compressibility.
  • microcrystallme cellulose Dibasic calcium phosphate, dihydrate, from about 2 to about 4: 1, preferably from about 2.6-3.1 : 1;
  • microcrystallme cellulose Calcium phosphate, anhydrous from about 1 to about 3: 1, preferably from about 1.6:
  • microcrystallme cellulose Tribasic calcium phosphate, from about 2 to about 4: 1, preferably from about 3.1 : 1.
  • a preferred disintegrating agent is sodium croscarmellose.
  • the sodium croscarmellose is present in an amount of about 2 to about 5% w/w.
  • a preferred lubricant is magnesium stearate.
  • An aspect of the present invention is a process for preparing a tablet formulation which comprises:
  • step (b) roller compression granulation of the mixture of step (a) for the purpose of preparing granules
  • step (d) lubricating the granulation from steb (b); d) compacting the lubricated granulates of step (c) into concave tablet; and e) film coating tablets from step (d).
  • Interleukin-23 is a heterodimeric cytokine comprised of two subunits, pl9 which is unique to IL-23, and p40, which is shared with IL-12.
  • the pl9 subunit is structurally related to IL-6, granulocyte-colony stimulating factor (G-CSF), and the p35 subunit of IL-12.
  • IL-23 mediates signaling by binding to a heterodimeric receptor, comprised of IL-23R and IL-12 i, which is shared by the IL-12 receptor.
  • Therapeutic antibodies may be used to block cytokine activity.
  • the most significant limitation in using antibodies as a therapeutic agent in vivo is the immunogenicity of the antibodies.
  • Most monoclonal antibodies are derived from rodents, repeated use in humans results in the generation of an immune response against the therapeutic antibody.
  • Such an immune response results in a loss of therapeutic efficacy at a minimum and a potential fatal anaphylactic response at a maximum.
  • mice injected with hybrids of human variable regions and mouse constant regions develop a strong anti-antibody response directed against the human variable region, suggesting that the retention of the entire rodent Fv region in such chimeric antibodies may still result in unwanted immunogenicity in patients.
  • CDR loops of variable domains comprise the binding site of antibody molecules. Therefore, the grafting of rodent CDR loops onto human frameworks (i.e., humanization) was attempted to further minimize rodent sequences. Jones et al. (1986) Nature 321 :522; Verhoeyen et al. (1988) Science 239:1534. However, CDR loop exchanges still do not uniformly result in an antibody with the same binding properties as the antibody of origin. Changes in framework residues (FR), residues involved in CDR loop support, in humanized antibodies also are required to preserve antigen binding affinity. Kabat et al. (1991) J. Immunol. 147: 1709.
  • the present invention involves antagonism of IL-23 activity as a means of ameliorating skin rash associated with treatment with PI3K/AKT pathway inhibitors, such as cancer therapy.
  • Any suitable method of antagonizing IL-23 activity can be used in the methods of the present invention. Such methods include blocking the expression or activity of IL-23 or its receptor.
  • the method of antagonizing IL-23 activity is a method that does not antagonize the activity of IL-12, e.g. by use of an IL-23 -specific antagonist.
  • Such methods of antagonizing IL-23 may involve blocking of the activity of the pl9 subunit of IL-23, rather than the p40 subunit, since the pl9 subunit is specific to IL-23 (pi 9 + p40) whereas the p40 subunit is shared with IL-12 (p35 + p40).
  • Such methods of antagonizing IL- 23 may also involve blocking of the activity of the IL-23R subunit of the IL-23 receptor complex (IL-23R + IL-12Rpi), rather than the IL-12Rpi subunit that is shared with the IL-12 receptor (IL-12Rpi + IL-12RP2).
  • IL-23 antagonists include, but are not limited to, small molecule compounds, antisense nucleic acids, small interfering nucleic acids, aptamers, antibodies or antigen binding fragments thereof, and soluble forms of IL-23 receptor.
  • the IL-23 antagonist is an IL-23 -specific antagonist.
  • Exemplary IL-23 -specific antagonists include an antibody that binds specifically to IL-23p40 but not IL-12p40 (US 7,247,711 to Centocor) or an antibody that makes contacts with both the pl9 and p40 subunits of IL-23 (WO 2011/056600 to Amgen, Inc.). Fibronectin-derived IL-23 antagonists are disclosed at WO 2011/103105 (developed at Adnexus Therapeutics Inc., now part of Bristol-Myers Squibb Co.).
  • the IL-23 -specific antagonist binds to pi 9.
  • IL-23 -specific antagonists that bind to pl9 include multimerized IL-23 receptors
  • IL-23 -specific antagonists that bind to pl9 include antibodies or antigen-binding fragments thereof that specifically bind to the pl9 subunit of IL-23, as disclosed at
  • Anti-IL-23pl9 antibodies that may be suitable for use in the methods of the present invention also include, but are not limited to, Merck's SCH 900222/MK-3222; Eli Lilly's LY2525623, and Centocor's CNTO 1959, all of which have entered human clinical trials. Specifically, the sequences of SEQ ID NOs: 48 and 52 (heavy chain variable domains), 57 (light chain variable domain), 28-37-40 (light chain CDRs 1-2-3, respectively) and 3-8-19 (light chain CDRs 1-2-3, respectively) of EP 1937721 Bl (to Eli Lilly and Company) are hereby incorporated by reference.
  • Centocor Centocor
  • the anti-IL-23pl9 antibodies, or antigen binding fragments thereof are based on antibody 13B8 of commonly assigned WO 2008/103432, the disclosure of which is hereby incorporated by reference in its entirety.
  • the anti-human IL- 23pl9 antibody may comprise one, two, three, four, five or six of the CDR sequences, or the heavy and light chain variable domains, of the humanized antibodies disclosed in commonly assigned WO 2008/103432, for example antibodies hul3B8a, b or c.
  • the anti-human IL-23pl9 antibody competes with antibody hul3B8a, b or c for binding to human IL-23.
  • the anti-human IL-23pl9 antibody binds to the same epitope on human IL-23 as hul3B8a, b or c.
  • a hybridoma expressing antibody 13B8 was deposited pursuant to the
  • the anti-human IL-23pl9 antibody is able to block binding of human IL-23pl9 to the antibody produced by the hybridoma deposited with accession number PTA-7803 in a cross-blocking assay.
  • the anti- human IL-23pl9 antibody binds to the same epitope as the antibody produced by the hybridoma deposited with ATCC under accession number PTA-7803.
  • the anti-human IL-23pl9 antibody comprises the same CDR sequences as the antibody produced by the hybridoma deposited with ATCC with accession number PTA- 7803.
  • the IL-23 -specific antagonist binds to IL-23R.
  • Exemplary IL-23 -specific antagonists that bind to IL-23R include anti-IL-23R antibodies (WO 2008/106134 and WO 2010/027767 to Schering Corp.); multimerized and multimerized polypeptides that binds to IL-23R (U.S. Pat. App. Pub. No. 2011/0086806 to Anaphore, Inc.); and IL-23 receptor antagonist peptides (WO 2009/007849 to Valorisation HSJ and Societe en Commandite), such as APG2305 (Allostera Pharma, Inc.).
  • the IL-23 antagonist is a non-specific IL-23 antagonist
  • Exemplary non-specific IL-23 antagonists include antibodies that bind to the p40 subunit of IL-23 and IL-12, such as ustekinumab (CNTO 1275) and briakinumab (ABT-874, J-695).
  • Ustekinumab is marketed by Centocor for the treatment of psoriasis, and is described at US 6,902,734 and US 7,166,285 (to Centocor, Inc.), the disclosures of which are hereby incorporated by reference in their entireties.
  • sequences of SEQ ID NOs: 7 (heavy chain variable domain) and 8 (light chain variable domain), of US 6,902,734 are hereby incorporated by reference.
  • SEQ ID NOs: 4-5-6 and 1-2-3 of US 6,902,734 are also incorporated by reference.
  • Sequences for ustekinumab are also provided at SEQ ID NOs: 51 - 60 of the sequence listing of the present application.
  • Briakinumab was developed by Abbott, and is described at US 6,914,128 and US 7,504,485, the disclosures of which are hereby incorporated by reference in their entireties. Specifically, the sequences of SEQ ID NOs: 31 (heavy chain variable domain), 32 (light chain variable domain) SEQ ID NOs; 30- 28-26 (light chain CDRs 1-2-3, respectively) and 29-27-25 (heavy chain CDRs 1-2-3, respectively) of US 6,914,128 are hereby incorporated by reference. Sequences for briakinumab are also provided at SEQ ID NOs: 61 - 70 of the sequence listing of the present application.
  • exemplary non-specific IL-23 antagonist antibodies that bind to the p40 subunit of IL-23 and IL-12 are disclosed at Clarke et al. (2010) mAbs 2: 1-11 (Cephalon Australia, Pty., Ltd.).
  • FM202 Femta Pharmaceuticals
  • FM202 is also a monoclonal antibody that binds to the p40 subunit of both IL-12 and IL-23, as are the antibodies disclosed at
  • WO 2010/017598 (Arana Therapeutics, Ltd.).
  • Apilimod mesylate (STA-5326, Synta Pharmaceuticals Corp.), an oral non-specific IL-23 antagonist, may also be used in some embodiments of the present invention.
  • Still further exemplary non-specific IL-23 antagonists include antibodies that bind to the IL-12Rpi subunit of both the IL-12 and IL-23 receptor complexes (WO 2010/112458 to Novartis AG).
  • amino acid sequence variants of the human or humanized anti-IL-23 antibody will have an amino acid sequence having at least 75% amino acid sequence identity with the original human or humanized antibody amino acid sequences of either the heavy or the light chain more preferably at least 80%, more preferably at least 85%, more preferably at least 90%), and most preferably at least 95, 98, or 99%.
  • Identity or homology with respect to this sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the human or humanized anti-IL-23 residues, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. None of N-terminal, C-terminal, or internal extensions, deletions, or insertions into the antibody sequence shall be construed as affecting sequence identity or homology.
  • the human or humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE.
  • the antibody is an IgG antibody.
  • Any isotype of IgG can be used, including IgGi, IgG 2 , IgG 3 , and IgG 4 .
  • Variants of the IgG isotypes are also contemplated.
  • the human or humanized antibody may comprise sequences from more than one class or isotype. Optimization of the necessary constant domain sequences to generate the desired biologic activity is readily achieved by screening the antibodies in the biological assays described below.
  • either class of light chain can be used in the compositions and methods herein.
  • kappa, lambda, or variants thereof are useful in the present compositions and methods.
  • any suitable portion of the CDR sequences from the non-human antibody can be used.
  • the CDR sequences can be mutagenized by substitution, insertion or deletion of at least one residue such that the CDR sequence is distinct from the human and non-human antibody sequence employed. It is contemplated that such mutations would be minimal.
  • at least 75% of the humanized antibody residues will correspond to those of the non-human CDR residues, more often 90%, and most preferably greater than 95%.
  • any suitable portion of the FR sequences from the human antibody can be used.
  • the FR sequences can be mutagenized by substitution, insertion or deletion of at least one residue such that the FR sequence is distinct from the human and non-human antibody sequence employed. It is contemplated that such mutations would be minimal.
  • at least 75% of the humanized antibody residues will correspond to those of the human FR residues, more often 90%, and most preferably greater than 95, 98, or 99%.
  • CDR and FR residues are determined according to the standard sequence definition of Kabat. Kabat et al. (1987) Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda Md.
  • SEQ ID NOs: 1-5 show the heavy chain variable domain sequences of various mouse anti-human IL-23pl9 antibodies, and SEQ ID NOs: 9-13 depict the light chain variable domain sequences.
  • FIGS. 1 and 2 provide sequence lineups of heavy and light chain variable domains of the various antibodies of the present invention.
  • CDRs are indicated in the figures, and the individual CDR sequences are each presented with unique Sequence Identifiers as indicated in Table 4.
  • 13B8 sequence (with kappa constant region) is provided at SEQ ID NO: 14, and the light chain variable domain comprises residues 1-108 of that sequence.
  • Three versions of the humanized heavy chain 13B8 sequence (with ⁇ constant regions) are provided at SEQ ID NOs: 6-8, and the heavy chain variable domain comprises residues 1-116 of those sequences.
  • the 13B8 heavy chains variants are illustrated at Table 3, with differences from the parental sequence noted in bold.
  • the Met (M) was modified to Lys (K) to avoid the potential for oxidation of the residue and inactivation of the antibody.
  • the substitution of AQKLQ for NEMFE is a replacement of the murine CDR sequence with the human germline sequence from the human framework selected to humanize the antibody.
  • Antibody CDRH2 Sequence SEQ ID NO: ml3B8, hl3B8-a QIFPASGSADYNEMFEG 24
  • Humanized forms of the other antibodies disclosed herein may be created by simply substituting the parental rodent antibody CDRs into the light and heavy chain sequences for humanized 13B8 provided at SEQ ID NOs: 14 and 6. This approach is most likely to be successful for antibody chains with CDRs having high homology with the CDRs of antibody 13B8, e.g. clone 1 ICl on the heavy chain and clones 1 ICl and 21D1 on the light chain.
  • the murine antibodies may be independently humanized using the approaches outlines herein, e.g. at Example 2.
  • CDRs include variants of any single sequence CDR disclosed herein (SEQ ID NOs: 15-46), in which the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more conservative amino acid substitutions relative to the disclosed sequence, as determined using the data of Table 1.
  • chimeric antibodies comprise a portion of the heavy and/or light chain identical with, or homologous to, corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity. See U.S. Pat. No. 4,816,567; and
  • Bispecific antibodies are also useful in the present methods and compositions.
  • bispecific antibody refers to an antibody, typically a monoclonal antibody, having binding specificities for at least two different antigenic epitopes, e.g., IL- 23pl9 and IL-17.
  • the epitopes are from the same antigen.
  • the epitopes are from two different antigens.
  • Methods for making bispecific antibodies are known in the art. For example, bispecific antibodies can be produced recombinantly using the co-expression of two immunoglobulin heavy chain/light chain pairs. See, e.g., Milstein et al. (1983) Nature 305: 537-39. Alternatively, bispecific antibodies can be prepared using chemical linkage. See, e.g., Brennan et al. (1985) Science 229:81.
  • Bispecific antibodies include bispecific antibody fragments. See, e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:6444-48, Gruber et al. (1994) J. Immunol. 152:5368.
  • different constant domains may be appended to the humanized V L and V R regions provided herein. For example, if a particular intended use of an antibody (or fragment) of the present invention were to call for altered effector functions, a heavy chain constant domain other than IgGl may be used.
  • IgGl antibodies provide for long half-life and for effector functions, such as complement activation and antibody-dependent cellular cytotoxicity, such activities may not be desirable for all uses of the antibody.
  • an IgG4 constant domain for example, may be used.
  • Antibodies having the characteristics identified herein as being desirable in a humanized anti-IL-23 antibody can be screened for inhibitory biologic activity in vitro or suitable binding affinity.
  • ANTIBODIES A LABORATORY MANUAL, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988) can be performed.
  • Antibodies that bind to the same epitope are likely to cross-block in such assays, but not all cross-blocking antibodies will necessarily bind at precisely the same epitope since cross-blocking may result from steric hindrance of antibody binding by antibodies bind at overlapping epitopes, or even nearby non-overlapping epitopes.
  • Biol. Chem. 270: 1388-1394 can be performed to determine whether the antibody binds an epitope of interest.
  • "Alanine scanning mutagenesis,” as described by Cunningham and Wells (1989) Science 244: 1081-1085, or some other form of point mutagenesis of amino acid residues in human IL-23 may also be used to determine the functional epitope for an anti-IL- 23 antibody of the present invention. Mutagenesis studies, however, may also reveal amino acid residues that are crucial to the overall three-dimensional structure of IL-23 but that are not directly involved in antibody-antigen contacts, and thus other methods may be necessary to confirm a functional epitope determined using this method.
  • the epitope bound by a specific antibody may also be determined by assessing binding of the antibody to peptides comprising fragments of human IL-23pl9 (SEQ ID NO: 47).
  • the sequence of the p40 subunit of IL-12 and IL-23 is found at GenBank Accession No. P29460.
  • a series of overlapping peptides encompassing the sequence of IL-23pl9 may be synthesized and screened for binding, e.g. in a direct ELISA, a competitive ELISA (where the peptide is assessed for its ability to prevent binding of an antibody to IL-23pl9 bound to a well of a microtiter plate), or on a chip.
  • Such peptide screening methods may not be capable of detecting some discontinuous functional epitopes, i.e. functional epitopes that involve amino acid residues that are not contiguous along the primary sequence of the IL-23pl9 polypeptide chain.
  • the epitope bound by antibodies of the present invention may also be determined by structural methods, such as X-ray crystal structure determination (e.g., WO2005/044853), molecular modeling and nuclear magnetic resonance (NMR)
  • crystallization may be accomplished using any of the known methods in the art (e.g. Giege et al. (1994) Acta Crystallogr.
  • a protein preparation having a concentration of at least about 1 mg/mL and preferably about 10 mg/mL to about 20 mg/mL.
  • Crystallization may be best achieved in a precipitant solution containing polyethylene glycol 1000-20,000 (PEG; average molecular weight ranging from about 1000 to about 20,000 Da), preferably about 5000 to about 7000 Da, more preferably about 6000 Da, with concentrations ranging from about 10% to about 30% (w/v). It may also be desirable to include a protein stabilizing agent, e.g. glycerol at a concentration ranging from about 0.5%) to about 20%>.
  • a suitable salt such as sodium chloride, lithium chloride or sodium citrate may also be desirable in the precipitant solution, preferably in a concentration ranging from about 1 mM to about 1000 mM.
  • the precipitant is preferably buffered to a pH of from about 4.0 to about 10.0, often from about 7.0 to 8.5, e.g. pH 8.0.
  • Specific buffers useful in the precipitant solution may vary and are well-known in the art. Scopes, Protein Purification: Principles and Practice, Third ed., (1994) Springer-Verlag, New York. Examples of useful buffers include, but are not limited to, HEPES, Tris, MES and acetate. Crystals may be grow at a wide range of temperatures, including 2°C, 4°C, 8°C and 26°C.
  • Antibody antigen crystals may be studied using well-known X-ray diffraction techniques and may be refined using computer software such as X-PLOR (Yale University, 1992, distributed by Molecular Simulations, Inc.; see e.g. Blundell & Johnson (1985) Meth. Enzymol. 114 & 115, H. W. Wyckoff et al. eds., Academic Press; U.S. Patent Application Publication No. 2004/0014194), and BUSTER (Bricogne (1993) Acta Cryst. D49:37-60; Bricogne (1997) Meth. Enzymol. 276A:361-423, Carter & Sweet, eds.; Roversi et al. (2000) Acta Cryst. D56: 1313-1323).
  • X-PLOR Yale University, 1992, distributed by Molecular Simulations, Inc.; see e.g. Blundell & Johnson (1985) Meth. Enzymol. 114 & 115
  • Additional antibodies binding to the same epitope as an antibody of the present invention may be obtained, for example, by screening of antibodies raised against IL-23 for binding to the epitope, or by immunization of an animal with a peptide comprising a fragment of human IL-23 comprising the epitope sequence.
  • Antibodies that bind to the same functional epitope might be expected to exhibit similar biological activities, such as blocking receptor binding, and such activities can be confirmed by functional assays of the antibodies.
  • Antibody affinities ⁇ e.g. for human IL-23) may be determined using standard analysis.
  • Preferred humanized antibodies are those which bind human IL-23pl9 with a Ka
  • the antibodies and fragments thereof useful in the present compositions and methods are biologically active antibodies and fragments.
  • biologically active refers to an antibody or antibody fragment that is capable of binding the desired the antigenic epitope and directly or indirectly exerting a biologic effect. Typically, these effects result from the failure of IL-23 to bind its receptor.
  • specific refers to the selective binding of the antibody to the target antigen epitope.
  • Antibodies can be tested for specificity of binding by comparing binding to IL-23 to binding to irrelevant antigen or antigen mixture under a given set of conditions. If the antibody binds to IL-23 at least 10, and preferably 50 times more than to irrelevant antigen or antigen mixture then it is considered to be specific.
  • An antibody that binds to IL-12 is not an IL-23- specific antibody.
  • An antibody that "specifically binds" to IL-23pl9 does not bind to proteins that do not comprise the IL-23pl9-derived sequences, i.e. "specificity" as used herein relates to IL-23pl9 specificity, and not any other sequences that may be present in the protein in question.
  • an antibody that "specifically binds" to IL-23pl9 will typically bind to FLAG ® -hIL-23pl9, which is a fusion protein comprising IL-23pl9 and a FLAG peptide tag, but it does not bind to the FLAG peptide tag alone or when it is fused to a protein other than IL-23pl9.
  • IL-23 -specific binding compounds of the present invention such as inhibitory
  • IL-23pl9 specific antibodies can inhibit its biological activity in any manner, including but not limited to production of IL- ⁇ and TNF by peritoneal macrophages and IL-17 by T R 17 T cells. See Langrish et al. (2004) Immunol. Rev. 202:96-105. Anti-IL-23pl9 antibodies will also be able to inhibit the gene expression of IL-17A, IL-17F, CCL7, CCL17, CCL20, CCL22, CCR1, and GM-CSF. See Langrish et al. (2005) J. Exp. Med. 201 :233-240.
  • IL-23-specific binding compounds of the present invention such as anti IL-23pl9 antibodies, will also block the ability of IL-23 to enhance proliferation or survival of T H 17 cells.
  • compositions including IL-23pl9 antibody the antibody (or antigen binding fragment thereof) is admixed with a
  • Formulations of therapeutic and diagnostic agents may be prepared by mixing with physiologically acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions.
  • physiologically acceptable carriers e.g., lyophilized powders, slurries, aqueous solutions or suspensions.
  • Toxicity and therapeutic efficacy of the antibody compositions, administered alone or in combination with an immunosuppressive agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 5 o (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio of LD 50 to ED 50 .
  • Antibodies exhibiting high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the mode of administration is not particularly important. Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal
  • parenteral delivery including intramuscular, intradermal, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • Administration of antibody used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, topical application or cutaneous, subcutaneous, intraperitoneal, parenteral, intraarterial or intravenous injection.
  • the liposomes will be targeted to and taken up selectively by the afflicted tissue.
  • an administration regimen for a therapeutic depends on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the immunogenicity of the entity, and the accessibility of the target cells in the biological matrix.
  • an administration regimen maximizes the amount of therapeutic delivered to the patient consistent with an acceptable level of side effects.
  • the amount of biologic delivered depends in part on the particular entity and the severity of the condition being treated. Guidance in selecting appropriate doses of antibodies, cytokines, and small molecules are available. See, e.g., Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub.
  • Determination of the appropriate dose is made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects.
  • Important diagnostic measures include those of symptoms of, e.g., the inflammation or level of inflammatory cytokines produced.
  • a biologic that will be used is substantially derived from the same species as the animal targeted for treatment (e.g. a humanized antibody for treatment of human subjects), thereby minimizing any immune response to the reagent.
  • Antibodies, antibody fragments, and cytokines can be provided by continuous infusion, or by doses at intervals of, e.g., one day, 1-7 times per week, one week, two weeks, monthly, bimonthly, quarterly, every 4 or 6 months, annually, etc.
  • Doses may be provided intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscular,
  • a preferred dose protocol is one involving the maximal dose or dose frequency that avoids significant undesirable side effects.
  • a total weekly dose is generally at least 0.05 ⁇ g/kg, 0.2 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 10 ⁇ g/kg, 100 ⁇ g/kg, 0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg body weight or more. See, e.g., Yang et al. (2003) New Engl. J. Med. 349:427-434; Herald et al. (2002) New Engl. J. Med. 346:1692-1698; Liu et al.
  • a small molecule therapeutic e.g., a peptide mimetic, natural product, or organic chemical
  • a small molecule therapeutic e.g., a peptide mimetic, natural product, or organic chemical, is about the same as for an antibody or polypeptide, on a moles/kg basis.
  • inhibit or “treat” or “treatment” includes a postponement of development of the symptoms associated with skin rash induced by PI3K/AKT pathway inhibitors and/or a reduction in the severity of such symptoms that will or are expected to develop.
  • the terms further include ameliorating existing uncontrolled or unwanted side effects, such as skin rash, and preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms.
  • the terms denote that a beneficial result has been conferred on a subject with a sign or symptom, or with the potential to develop such a sign or symptom.
  • Prevent refers to a reduction or complete elimination of a side effect, such as a skin rash, prior to it manifesting at all. Neither treatment nor prevention, as used herein, requires complete elimination of signs and symptoms. Prevention and treatment refer to any clinically meaningful improvement of the relevant condition, such as reduction in the signs or symptoms of skin rash associated with treatment with PI3K/AKT inhibitors.
  • the term "therapeutically effective amount” or “effective amount” refers to an amount of an IL-23 antagonist, e.g. an IL-23pl9-specific antibody, or antigen binding fragment thereof, that when administered alone or in combination with an additional therapeutic agent to a cell, tissue, or subject is effective to prevent or ameliorate the drug-induced side effect, such as skin rash.
  • a therapeutically effective dose further refers to that amount of the compound sufficient to result in amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
  • a therapeutically effective dose refers to that ingredient alone.
  • a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • An effective amount of therapeutic will decrease the symptoms typically by at least 10%; usually by at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably by at least 50%.
  • Typical veterinary, experimental, or research subjects include monkeys, dogs, cats, rats, mice, rabbits, guinea pigs, horses, and humans.
  • the nucleic acids encoding the two chains are isolated and inserted into one or more replicable vectors for further cloning (amplification of the DNA) or for expression.
  • DNA encoding the monoclonal antibody is readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).
  • Many vectors are available.
  • the vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence.
  • both the light and heavy chains of the humanized anti-IL-23pl9 antibody of the present invention are expressed from the same vector, e.g. a plasmid or an adenoviral vector.
  • Antibodies of the present invention may be produced by any method known in the art.
  • antibodies are expressed in mammalian or insect cells in culture, such as Chinese hamster ovary (CHO) cells, human embryonic kidney (HEK) 293 cells, mouse myeloma NSO cells, baby hamster kidney (BHK) cells, Spodoptera frugiperda ovarian (Sf9) cells.
  • CHO Chinese hamster ovary
  • HEK human embryonic kidney
  • BHK baby hamster kidney
  • Spodoptera frugiperda ovarian (Sf9) cells In one embodiment, antibodies secreted from CHO cells are recovered and purified by standard chromatographic methods, such as protein A, cation exchange, anion exchange, hydrophobic interaction, and hydroxyapatite chromatography. Resulting antibodies are concentrated and stored in 20 mM sodium acetate, pH 5.5.
  • the antibodies of the present invention are produced in yeast, e.g. according to the methods described in WO 2005/040395. Briefly, vectors encoding the individual light or heavy chains of an antibody of interest are introduced into different yeast haploid cells, e.g. different mating types of the yeast Pichia pastoris, which yeast haploid cells are optionally complementary auxotrophs. The transformed haploid yeast cells can then be mated or fused to give a diploid yeast cell capable of producing both the heavy and the light chains. The diploid strain is then able to secret the fully assembled and biologically active antibody.
  • the relative expression levels of the two chains can be optimized, for example, by using vectors with different copy number, using transcriptional promoters of different strengths, or inducing expression from inducible promoters driving transcription of the genes encoding one or both chains.
  • the respective heavy and light chains of a plurality of different anti-IL-23pl9 antibodies are introduced into yeast haploid cells to create a library of haploid yeast strains of one mating type expressing a plurality of light chains, and a library of haploid yeast strains of a different mating type expressing a plurality of heavy chains.
  • These libraries of haploid strains can be mated (or fused as spheroplasts) to produce a series of diploid yeast cells expressing a combinatorial library of antibodies comprised of the various possible permutations of light and heavy chains.
  • the combinatorial library of antibodies can then be screened to determine whether any of the antibodies has properties that are superior (e.g. higher affinity for IL-23) to those of the original antibodies. See. e.g., WO 2005/040395.
  • antibodies of the present invention are human domain antibodies in which portions of an antibody variable domain are linked in a polypeptide of molecular weight approximately 13 kDa. See, e.g., U.S. Pat. Publication No. 2004/0110941.
  • Such single domain, low molecular weight agents provide numerous advantages in terms of ease of synthesis, stability, and route of administration.
  • the present invention provides methods for preventing and/or treating skin rash that may occur as a side effect of treatment with PI3K/AKT pathway inhibitors.
  • the methods of the present invention involve antagonism of IL-23, e.g. by treatment with an IL- 23 antagonist, in any subject being treated with a PI3K/AKT pathway inhibitor for any reason.
  • PI3K/AKT pathway inhibitors may find use not only in the treatment of cancer or tumors, but also in the treatment of diseases in which angiogenesis is implicated, such as ocular neovascular diseases like diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, age-related macular degeneration (WO 00/30651); atherosclerosis, osteoarthritis (WO 03/035048), psoriasis, obesity, and Alzheimer's disease.
  • PI3K/AKT pathway inhibitors may find use in treating hyperproliferative disorders like restenosis (WO 03/032809), inflammation, autoimmune diseases and allergy/asthma.
  • IL-23 antagonists may find use in the manufacture of medicaments for preventing and/or treating skin rash that may occur as a side effect of treatment with a PI3K/AKT pathway inhibitor.
  • the present invention further relates to an IL-23 antagonist, e.g. an anti-IL-23 antibody, for use in preventing and/or treating skin rash that may occur as a side effect of treatment with a PI3K/AKT pathway inhibitor.
  • the invention further relates to prevention and/or treatment of a disorder, such as cancer or a tumor, by administering to a subject an IL-23 antagonist and a PI3K/AKT inhibitor.
  • the IL-23 antagonist is administered prior to, concurrently with, or after administration of the PI3K/AKT inhibitor.
  • Administration of the IL-23 antagonist prior to or concurrently with the PI3K/AKT inhibitor may be helpful in preventing a PI3K/AKT inhibitor-induced rash, whereas administration of the IL-23 antagonist after the onset of a PI3K/AKT inhibitor-induced rash may be helpful in treatment of the rash or prevention of a rash before is has occurred.
  • the IL-23 antagonist is administered, e.g., 1 hour, 12 hours, 1, 2, 4, 7, 10, 14, 21, 30 or more days prior to administration of the PI3K/AKT inhibitor.
  • the IL-23 antagonist is an anti-IL-23pl9 antibody or antigen binding fragment thereof.
  • the PI3K/AKT inhibitor is naphthyridine compound, e.g., 8-[4-(l-aminocyclobutyl)phenyl]-9- phenyl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-3(2H)-one (MK-2206).
  • PI3K/AKT inhibitors of the present invention may be any PI3K/AKT inhibitors.
  • the methods of the present invention find particular value at doses that are high enough to otherwise induce a rash in subjects.
  • 8-[4-(l- aminocyclobutyl)phenyl]-9-phenyl[l,2,4]triazolo[3,4-f]-l,6-naphthyridin-3(2H)-one may be administered at 150 - 200 mg every week, such as 200 mg every week, or at doses that increase the risk of skin rash, such as 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10,000 mg or more.
  • IL-23 antagonist of the present invention may be administered at any dose effective to prevent or treat a rash induced by a PI3K/AKT pathway inhibitor.
  • Anti-IL-23 antibodies such as anti-IL-23pl9 and anti-IL-23p40 antibodies, made be administered, e.g., at 0.01, 0.03, 0.1, 0.3, 0.5, 1, 3, 5, 10, 30, 50 or 100 mg/kg or more.
  • the anti-IL-23 antibody (or fragment) is administered at 0.1, 0.3, 1 or 3 mg/kg.
  • the anti-IL-23 antibody (or fragment) is administered weekly, biweekly, monthly, bimonthly, every three months or at other intervals.
  • the IL-23 antibody (or fragment) is administered only once during a given course of treatment with a PI3K AKT pathway inhibitor, or is administered as needed based on an evaluation of the condition of a specific subject, e.g. based on the presence and severity of a skin rash.
  • Anti- IL-23 antibodies (or fragments thereof) may be administered by any suitable means, including but not limited to subcutaneous injection and intravenous infusion.
  • Exemplary substituted naphthyridine compounds for use as AKT inhibitors in the methods of the present invention may be synthesized as follow. See, e.g., WO 2008/070016 (Schemes 1C and IE).
  • Trifluoroacetic acid (17.4 mL, 234 mmol) was added carefully to a stirred mixture of Boc aldehyde 1-7 (20 g, 78.1 mmol) and dichloromethane (60 mL) keeping the temperature below 25 °C. The solution was warmed to 35 °C, aged overnight (vigorous off- gassing) and then cooled to room temperature. 25 mL of MTBE was added and the resulting white slurry was aged for one hour, filtered, and the filter cake rinsed with MTBE (10 mL x 2). Solid 1-8 TFA salt was dried under vacuum. tert-butyl ⁇ l-[4-(5-chloro-3-phenyl-l,6-naphthyridin-2-yl)phenyl]cyclobutyl ⁇ carbamate (1-9)
  • a stirred slurry of chloronapthyridine 1-9 (1.8 g), methyl hydrazine carboxylate (0.318 g) and isopropanol (20 L) is warmed to 66 °C before becoming homogeneous.
  • 5-6 N HC1 in IPA (0.05 ml) is added and the temperature is increased to 70 °C for 16 hours and then is cooled to RT.
  • 45wt% potassium hydroxide solution (0.52 mL) is mixed with water (5.5 mL) and added over 15 minutes. After 30 minutes, aqueous acetic acid (0.7 mL in 6 mL water) is added followed by water (2 mL).
  • a mono-HCl version of MK-2206 was also produced via dissolution in water.
  • THP-1 levels were determined as follows. THP-1 monocytic cells were cultured at 1 x 10 6 cells/ml in 24-well plates in RPMI 1640 complete medium. Cells were pre-treated with either of two AKT inhibitors (MK-2206 and AKTi-X) at 0.1 ⁇ or 0.5 ⁇ for 1 hour.
  • MK-2206 and AKTi-X AKT inhibitors
  • IL-23 is a heterodimeric complex of p40 and pl9
  • IL-12 is a heterodimeric complex of p40 and p35 subunits. Results are shown in FIG. 3.
  • AKT inhibitor specifically enhances IL-23 subunit gene expression above the level induced by LPS alone. This result holds true for both AKT inhibitors (MK-2206 and AKTi-X). These results are consistent with a downstream role for IL-23 in AKT inhibitor-induced skin rash.
  • CD 14+ cells were isolated from healthy human donors (4 donors total).
  • PBMC were isolated from buffy coats using Ficoll gradient procedure followed by negative selection of CD 14+ cells using
  • Monocyte Isolation Kit II (Miltenyi Biotec Cat # 130-091-153). CD14+ cells were grown in complete DMEM medium supplemented with antibiotics. Cells were pre-treated with either of two AKT inhibitors (MK-2206 and AKTi-X) at 0.1 ⁇ or 0.5 ⁇ for lh. Ten (10) ⁇ lipopolysaccharide (LPS) was then added for 3h, 6h or 24h, at which time cells were harvested for R A extraction and TAQMAN ® real-time quantitative polymerase chain reaction gene expression analysis. Results are shown in FIG. 4. Supernatants were also collected for IL-23 protein determination. See Example 5.
  • AKT inhibitors MK-2206 and AKTi-X
  • LPS lipopolysaccharide
  • AKT inhibitor specifically enhances IL-23 subunit gene expression above the level induced by LPS alone. This result holds true for both donors, and at time points ranging from 3 to 6 to 24 hours post-treatment (other than the single datapoint for Donor 2 at 24 hours). These results are consistent with a downstream role for IL-23 in AKT inhibitor-induced skin rash.
  • PBMCs as a function of treatment with TLR agonists, with or without AKT inhibitor was determined using culture supernatants prepared as described in Example 4.
  • IL-23 was detected in an electrochemilummescence assay (ECL) using an anti-human IL-23pl9 capture antibody and a ruthenium labeled anti-human IL-12/23p40 detection antibody. Results are shown in FIG. 5.
  • the levels of expression of 24 genes known to be modulated by IL-23 were determined in IL-23 -treated cynomolgus monkeys and also in MK-2206-treated rhesus monkeys as follows.
  • IL-23 -induced skin inflammation model 10 or 100 ⁇ g of human IL-23 was intradermally injected to the skin of cynomolgus monkeys each day for 14 days to induce skin inflammation.
  • AKTi skin rash model 54 or 108 mg of MK-2206 was delivered orally to rhesus monkeys daily for 14 - 28 days to induce skin rash. Skin samples were then collected from monkeys for histological and gene expression analyses.
  • Gene expression results for the AKTi skin rash model are provided at Table 2, and representative gene expression data for selected genes in both the IL-23 and AKTi models are provided in FIGS. 6A and 6B.
  • Anti-IL-23pl9 treatment is repeated at approximately 28-day intervals over the course of MK-2206 treatment. Treatment with MK-2206 is continued until the desired therapeutic endpoint is reached, or dose limiting toxicity arises.
  • Grade 2 skin rash involves macular or papular eruption or erythema with pruritis or other associated symptoms, and localized desquamation or other lesions covering less than half of the body surface area.
  • Grade 3 skin rash involves severe, generalized erythroderma or macular, popular or vesicular eruption, and desquamation covering half of the body surface area or more.
  • Grade 4 rash involves generalized exfoliative, ulcerative, of bulluous dermatitis.
  • Anti-IL-23pl9 treatment if necessary, is repeated at approximately 28-day intervals over the course of MK-2206 treatment. Treatment with MK-2206 is continued until the desired therapeutic endpoint is reached, or dose limiting toxicity arises.
  • Anti-IL-23pl9 treatment is repeated at approximately 28-day intervals over the course of MK-2206 treatment. Treatment with MK-2206 is continued until the desired therapeutic endpoint is reached, or dose limiting toxicity arises.
  • Grade 2 skin rash involves macular or papular eruption or erythema with pruritis or other associated symptoms, and localized desquamation or other lesions covering less than half of the body surface area.
  • Grade 3 skin rash involves severe, generalized erythroderma or macular, popular or vesicular eruption, and desquamation covering half of the body surface area or more.
  • Grade 4 rash involves generalized exfoliative, ulcerative, of bulluous dermatitis.
  • Anti-IL-23pl9 treatment if necessary, is repeated at approximately 28-day intervals over the course of MK-2206 treatment. Treatment with MK-2206 is continued until the desired therapeutic endpoint is reached, or dose limiting toxicity arises.
  • Table 4 provides a brief description of the sequences in the sequence listing.

Abstract

La présente invention concerne des méthodes d'utilisation d'antagonistes de l'interleukine 23 (IL-23) en vue du traitement ou de la prévention d'éruptions cutanées associées à un traitement par des inhibiteurs de la voie PI3K/AKT, par exemple un traitement anticancéreux.
EP12811568.0A 2011-07-08 2012-07-03 Antagonistes de l'il-23 utilisables en vue du traitement ou de la prévention d'éruptions cutanées associées à un traitement par des inhibiteurs de la voie pi3k/akt Withdrawn EP2729174A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201161505946P 2011-07-08 2011-07-08
US201161547549P 2011-10-14 2011-10-14
PCT/US2012/045363 WO2013009535A1 (fr) 2011-07-08 2012-07-03 Antagonistes de l'il-23 utilisables en vue du traitement ou de la prévention d'éruptions cutanées associées à un traitement par des inhibiteurs de la voie pi3k/akt

Publications (1)

Publication Number Publication Date
EP2729174A1 true EP2729174A1 (fr) 2014-05-14

Family

ID=47506410

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12811568.0A Withdrawn EP2729174A1 (fr) 2011-07-08 2012-07-03 Antagonistes de l'il-23 utilisables en vue du traitement ou de la prévention d'éruptions cutanées associées à un traitement par des inhibiteurs de la voie pi3k/akt

Country Status (2)

Country Link
EP (1) EP2729174A1 (fr)
WO (1) WO2013009535A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10987336B2 (en) 2018-04-16 2021-04-27 Onquality Pharmaceuticals China Ltd. Method of preventing or treating side effect of tumor therapy

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG10202005315SA (en) * 2014-08-19 2020-07-29 Nat Univ Corporation Okayama Univ Agent for treating and/or preventing diseases associated with immune abnormalities by combining biguanide antidiabetic drug with immunosuppressive factor blocking agent or costimulatory receptor agonist
WO2019114705A1 (fr) 2017-12-13 2019-06-20 上海小午医药科技有限公司 Méthode de prévention ou de traitement d'une maladie associée à l'inhibition du récepteur du facteur de croissance épidermique (regf)
EP3793521A4 (fr) 2018-05-18 2022-02-23 Janssen Biotech, Inc. Méthode sûre et efficace de traitement du lupus avec un anticorps anti-il12/il23
CN113825765A (zh) * 2019-03-14 2021-12-21 詹森生物科技公司 用于制备抗il12/il23抗体组合物的制造方法
EA202192459A1 (ru) * 2019-03-18 2021-11-25 Янссен Байотек, Инк. Способ лечения псориаза антителом к il12/il23 у субъектов детского возраста
WO2023186060A1 (fr) * 2022-03-31 2023-10-05 InventisBio Co., Ltd. Inhibiteurs de kinase, leurs procédés de préparation et leurs utilisations

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2367302T3 (es) * 2002-12-23 2011-11-02 Schering Corporation Usos de la citoquina il-23 de mamífero; reactivos relacionados.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2013009535A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10987336B2 (en) 2018-04-16 2021-04-27 Onquality Pharmaceuticals China Ltd. Method of preventing or treating side effect of tumor therapy

Also Published As

Publication number Publication date
WO2013009535A1 (fr) 2013-01-17

Similar Documents

Publication Publication Date Title
EP3317301B1 (fr) Polythérapies comprenant des molécules d'anticorps dirigées contre lag-3
EP2729174A1 (fr) Antagonistes de l'il-23 utilisables en vue du traitement ou de la prévention d'éruptions cutanées associées à un traitement par des inhibiteurs de la voie pi3k/akt
JP2020504095A (ja) 抗ＰＤ−Ｌ１抗体との組み合わせのための抗Ｔｉｍ−３抗体
JP2020504171A (ja) 抗ＰＤ−１抗体との組み合わせのための抗Ｔｉｍ−３抗体
EA019595B1 (ru) СПЕЦИФИЧНЫЕ ИНГИБИТОРЫ PDGFRβ
CN111182919A (zh) 抗cd137抗体
EP3119806B1 (fr) Anticorps il -21
US20150266967A1 (en) Superior efficacy of cd37 antibodies in cll blood samples
EP2951205B1 (fr) Composés anti-activine pour le traitement du cancer des ovaires
CN110636861B (zh) 用于治疗癌症的包含小分子csf-1r抑制剂和特异性地结合cd40的激动性抗体的协同疗法
AU2013254690B2 (en) Anti-PDGF-C antibodies
TW202144410A (zh) 抗介白素－３３抗體及其用途
TW201438737A (zh) Ｈｇｆ抗體之治療用途
EP3416983B1 (fr) Anticorps pour il-17c
WO2018075304A1 (fr) Anticorps de récepteur de tgfbêta ii
KR20180042335A (ko) 조합 및 이의 용도
CN113166239A (zh) 抗il-17a抗体及其应用
EP4115904A2 (fr) Anticorps anti-rspo3
TW201716439A (zh) Ｈｅｒ３抗體
TW202116804A (zh) 以ｐｄ－１／ｃｄ３雙特異性蛋白質所進行之血液性癌症治療
EP4186526A1 (fr) Agent pour inverser la résistance à des médicaments anticancéreux
US11773160B1 (en) Immune-stimulating IL-2 fusion proteins
US20240158491A1 (en) Immune-stimulating il-2 fusion proteins
WO2023165561A1 (fr) Anticorps anti-cd39 et leur utilisation
CN117940452A (zh) 用于治疗癌症的方法和组合物

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20140210

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20140811