WO2025076251A1 - Dosages d'inhibiteurs d'il-23 et de tnf-alpha destinés à être utilisés dans des troubles auto-immuns et inflammatoires - Google Patents

Dosages d'inhibiteurs d'il-23 et de tnf-alpha destinés à être utilisés dans des troubles auto-immuns et inflammatoires Download PDF

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WO2025076251A1
WO2025076251A1 PCT/US2024/049834 US2024049834W WO2025076251A1 WO 2025076251 A1 WO2025076251 A1 WO 2025076251A1 US 2024049834 W US2024049834 W US 2024049834W WO 2025076251 A1 WO2025076251 A1 WO 2025076251A1
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tnf
alpha
inhibitor
effective amount
therapeutically effective
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Brian Talmadge Dorsey
Carlos A. SATTLER
Sara H. BARBAT
Pamela Christine WEDEL
Jacqueline Michelle BENSON
Ciara Alice KENNEDY
Marcus Charles WEBB
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Sorriso Pharmaceuticals Inc
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Sorriso Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/50—Fusion polypeptide containing protease site

Definitions

  • autoimmune and inflammatory diseases such as inflammatory bowel disease (IBD) which includes Crohn’s disease and ulcerative colitis
  • IBD inflammatory bowel disease
  • GI gastrointestinal
  • Cytokines have been discovered to play a critical role in the pathogenesis of autoimmune diseases and inflammatory conditions of the GI tract.
  • IL interleukin
  • TNF-alpha tumor necrosis factor alpha
  • IL-23 and/or TNF-alpha blockade can be effective in ameliorating autoimmune and inflammatory conditions in the GI tract.
  • Pre-clinical and clinical data also suggest that the treatment regimen of IL-23 and/or TNF-alpha blockade can WSGR Docket No.60790-714.601 impact the efficacy and durability of clinical response.
  • Treatment regimen parameters include, but are not limited to, the administration route, the treatment schedule, and the therapeutic dosage. Varying the dosage administered to patients can be important in tuning therapeutic efficacy and reducing unwanted side effects.
  • Described herein in one aspect is a method of treating an autoimmune or inflammatory condition of the gastrointestinal tract in an individual in need thereof, the method comprising administering a therapeutically effective amount of an inhibitor of interleukin-23 (IL-23) and tumor necrosis factor alpha (TNF-alpha) to the individual, wherein the therapeutically effective amount is from about 100 milligrams to about 11,000 milligrams.
  • the inhibitor of IL-23 and TNF-alpha is administered orally.
  • the inhibitor of IL-23 and TNF-alpha is administered once a day.
  • the inhibitor of IL-23 and TNF-alpha is administered twice a day.
  • the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is from about 135 milligrams to about 3,645 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 135 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL- 23 and TNF-alpha is about 405 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 1,215 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 3,645 milligrams.
  • the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 10,935 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 100 milligrams to about 2,500 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 100 milligrams to about 1,200 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL- 23 and TNF-alpha is about 200 milligrams to about 1,200 milligrams.
  • the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 300 milligrams to about 1,200 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 350 milligrams to about 1,200 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL- 23 and TNF-alpha is about 400 milligrams to about 1,200 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 300 milligrams to about 2,500 milligrams.
  • the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 300 milligrams to about 2,000 WSGR Docket No.60790-714.601 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL- 23 and TNF-alpha is about 300 milligrams to about 1,800 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 300 milligrams to about 1,600 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 300 milligrams to about 1,400 milligrams.
  • the therapeutically effective amount of the inhibitor of IL- 23 and TNF-alpha is about 300 milligrams to about 1,300 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 300 milligrams to about 1,100 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 100 milligrams to about 1,250 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL- 23 and TNF-alpha is about 200 milligrams to about 1,250 milligrams.
  • the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 300 milligrams to about 1,250 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 350 milligrams to about 1,250milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is about 400 milligrams to about 1,250 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is at least about 300 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is at least about 400 milligrams.
  • the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is at least about 800 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL- 23 and TNF-alpha is at least about 1,200 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is at most about 2,500 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF- alpha is at most about 2,000 milligrams. In certain embodiments, the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha is at most about 1,500 milligrams.
  • the inhibitor of IL-23 and TNF-alpha comprises a multispecific polypeptide comprising a first antigen binding domain that binds to TNF-alpha and a second antigen binding domain that binds to IL-23.
  • the first antigen binding domain that binds to TNF-alpha comprises a VHH.
  • the second antigen binding domain that binds to IL-23 comprises a VHH.
  • the first antigen binding domain that binds to TNF-alpha and the second antigen binding domain that binds to IL-23 are coupled by a linker.
  • linker is a protease cleavable WSGR Docket No.60790-714.601 linker.
  • the linker is a polypeptide linker.
  • the linker is a polypeptide linker comprising an amino acid sequence as set forth in SEQ ID NO: 302.
  • the first antigen binding domain that binds to TNF-alpha comprises: a) a complementarity determining region 1 (CDR1) as set forth in SEQ ID NOs: 101, 107, 108, or 119; b) a complementarity determining region 2 (CDR2) as set forth in SEQ ID NOs: 102, 109 to 117, or 120; and/or c) a complementarity determining region 3 (CDR3) as set forth in SEQ ID NOs: 103 to 106 or 121 to 124.
  • CDR1 complementarity determining region 1
  • CDR2 complementarity determining region 2
  • CDR3 complementarity determining region 3
  • the first antigen binding domain that binds to TNF-alpha comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to any one of SEQ ID NOs: 118 or 125.
  • the second antigen binding domain that binds to IL-23 comprises: a) a complementarity determining region 1 (CDR1) as set forth in SEQ ID NOs: 1, 4, or 7; b) a complementarity determining region 2 (CDR2) as set forth in SEQ ID NOs: 2, 5, or 8; and/or c) a complementarity determining region 3 (CDR3) as set forth in SEQ ID NOs: 3, 6, or 9.
  • the second antigen binding domain that binds to IL-23 comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to any one of SEQ ID NOs: 10 to 12.
  • the inhibitor of IL-23 and TNF-alpha comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 201.
  • the inhibitor of IL-23 and TNF-alpha comprises an amino acid sequence that is at least 85%, 90%, 95%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 202.
  • the autoimmune or inflammatory condition comprises an inflammatory bowel disease.
  • the inflammatory bowel disease comprises ulcerative colitis.
  • the inflammatory bowel disease comprises Crohn’s disease.
  • the inflammatory bowel disease comprises immune checkpoint inhibitor associated colitis.
  • the inflammatory bowel disease comprises pouchitis.
  • the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha achieves at least about 400 nanogram per milliliter (ng/mL) of the first antigen binding domain that binds to TNF-alpha and at least about 400 nanogram per milliliter (ng/mL) of the second antigen binding domain that binds to IL-23 in the feces of the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 75,000 ng/mL of the first antigen binding domain that binds to TNF- alpha and at least about 20,000 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual at about 24 to 48 hours after administering the therapeutically WSGR Docket No.60790-714.601 effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 2,000 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 1,800 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 48 to 72 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF- alpha achieves at least about 40,000 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 32,000 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 24 to 48 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF- alpha achieves at least about 1,800 ng/mL of the first antigen binding domain that binds to TNF- alpha and at least about 3,800 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 48 to 72 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • a total cumulative fraction of the inhibitor of IL-23 and TNF-alpha eliminated in the feces of the individual is at most about 0.0002%, wherein a total cumulative fraction of the first antigen binding domain that binds to TNF-alpha (FeTot,TNF%) is at least about 2.00%, and wherein a total cumulative fraction of the second antigen binding domain that binds to IL-23 eliminated in the feces of the individual (Fe Tot,IL %) is at least about 1.00%.
  • FeTot,TNF% is at least about 10,000 times greater than FeTot,IL-TNF%, and wherein FeTot,IL% is at least about 5,000 times greater than FeTot,IL-TNF%.
  • a total cumulative fraction of the inhibitor of IL-23 and TNF-alpha eliminated in the feces of the individual is at most about 0.0002%, wherein a total cumulative fraction of the first antigen binding domain that binds to TNF-alpha (FeTot,TNF%) is at least about 2.00%, and wherein a total cumulative fraction of the second antigen binding domain that binds to IL-23 eliminated in the feces of the individual (Fe Tot,IL %) is at least about 0.40%.
  • FIGURE 1A illustrates a schematic of a single-domain heavy chain antibody (VHH) comprising four framework regions (FRs) and three complementarity determining regions (CDRs).
  • VHH single-domain heavy chain antibody
  • FRs framework regions
  • CDRs complementarity determining regions
  • FIGURE 1B illustrates a schematic of a construct comprising two identical VHHs joined by a linker, with each VHH comprising four framework regions (FRs) and three complementarity determining regions (CDRs).
  • FIGURE 1C illustrates a schematic of a construct comprising two distinct VHHs joined by a linker, with each VHH comprising four framework regions (FRs) and three complementarity determining regions (CDRs).
  • FIGURE 2 demonstrates that a bispecific anti-TNF–alpha/anti-IL–23 domain antibody (“TNF-alpha/IL-23 dual inhibitor”) and its liberated monomer arms can retain full anti- TNF–alpha and anti-IL–23 activity after exposure to trypsin and high levels of anti-TNF–alpha and anti-IL–23 activity after exposure to human fecal supernatant.
  • FIGURE 2A shows cleavage of the central lysine in TNF-alpha/IL-23 dual inhibitor. TNF-alpha/IL-23 dual inhibitor was incubated at 37 °C with 1/1,000 diluted faecal supernatant (HFS).
  • HFS 1/1,000 diluted faecal supernatant
  • FIGURE 2B shows inhibition curves assessed by ELISAs wherein binding molecules competed with biotinylated adalimumab (anti-TNF–alpha IgG1).
  • TNF-alpha/IL-23 dual inhibitor and the trypsin-liberated anti-TNF-alpha monomer arm (“liberated–anti-TNF”) were tested alongside the anti-TNF–alpha single domain antibody (“TNF-alpha inhibitor”) parent in a biotinylated adalimumab competition ELISA, where biotinylated adalimumab alone was used as a control.
  • FIGURE 2C shows inhibition curves assessed by ELISAs wherein binding molecules competed interrupted IL-23/IL-23-receptor binding.
  • TNF-alpha/IL-23 dual inhibitor and the trypsin- liberated anti-IL-23 monomer arm (“liberated–anti-IL-23”) were tested alongside the anti-IL–23 WSGR Docket No.60790-714.601 single domain antibody (“IL-23 inhibitor”) parent in the IL-23/IL-23R ELISA, where IL-23 alone was used as a control.
  • FIGURE 2D shows functional activity retention of TNF-alpha/IL- 23 dual inhibitor and its cleavage products after exposure to HFS.
  • TNF-alpha/IL-23 dual inhibitor and the parent monomers, TNF-alpha inhibitor and IL-23 inhibitor were incubated in pooled human fecal supernatant (HFS) for 4 hours.
  • FIGURE 2E and FIGURE 2F show TNF-alpha inhibitor– and IL-23-inhibitor–mediated inhibition, alone and in combination, of phosphorylation signals in ulcerative colitis (UC) colonic human biopsies.
  • Biopsies were collected from four different UC patients and incubated for 24 hours with single domain antibody treatments (Control (ID2A) 225 nM; TNF-alpha inhibitor 75 nM; IL-23 inhibitor 150 nM; or TNF-alpha inhibitor 75 nM + IL-23 inhibitor 150 nM combined) and analyzed for the extent of phosphorylation of tyrosine kinase receptors and signalling proteins that can be increased in inflamed intestinal tissue. Heatmap shadings were applied relative to the averaged signal of each phosphoprotein in the final array data set. Light shading indicates strong phosphorylation signals; dark shading indicates weak phosphorylation signals.
  • FIGURE 3 shows the pharmacokinetics of TNF-alpha/IL-23 dual inhibitor, the liberated anti-TNF–alpha monomer arm (“liberated–anti-TNF”), and the liberated anti-IL–23 monomer arm (“liberated–anti-IL-23”).
  • 10 non-human primates (NHPs) were dosed orally twice a day for 42 days (135 mg/dose, 270 mg per day total).
  • TNF-alpha/IL-23 dual inhibitor On Day 42, fecal samples of cynomolgus monkeys were collected at 6-hour timepoints following the first daily dose of TNF-alpha/IL-23 dual inhibitor for 10 animals during the first 24 hours after dosing and for 4 animals for an additional 24 hours (two 12-hour sample collection time points).6 animals were given a third oral dose of TNF-alpha/IL-23 dual inhibitor at the 24-hour time point and culled 4 hours after this final dose for intestinal analysis. Intact TNF-alpha/IL-23 dual inhibitor levels were below the assay lower limit of quantitation (245nM) in all intestinal samples, therefore fecal samples were not analyzed for intact TNF-alpha/IL-23 dual inhibitor.
  • FIGURE 3A shows the concentration of liberated–anti-TNF and liberated–anti-IL-23 in fecal samples at various timepoints.
  • FIGURE 3B shows the concentration of liberated–anti-TNF and liberated–anti-IL- 23 in intestinal samples of cynomolgus monkeys. The animals were culled 4 hours after the third dose, and intestinal contents were collected at this 4-hour time point.
  • FIGURE 5 shows the pharmacokinetics of TNF-alpha/IL-23 dual inhibitor and its corresponding liberated anti-TNF–alpha and anti-IL–23 monomer arms in fecal samples collected from individuals administered with a single dose of TNF-alpha/IL-23 dual inhibitor at varying dosages from various time points post-oral administration. Minimal level of detection is indicated as “MLD”.
  • FIGURE 5A shows the pharmacokinetics of TNF-alpha/IL-23 dual inhibitor in fecal samples collected from individuals dosed orally at 135 mg, 405 mg, 1215 mg, and 3645 mg doses from various time points post-oral administration. Arithmetic mean concentrations and individual points are plotted.
  • FIGURE 5B shows the pharmacokinetics of liberated–anti-IL-23 in fecal samples collected from individuals dosed orally at 135 mg, 405 mg, 1215 mg, and 3645 mg doses from various time points post-oral administration. Median concentrations and individual data points are plotted. Only positive points were included in mean calculation and in the figure unless all data points for a given day were below the lower limit of quantification.
  • FIGURE 6 shows the pharmacokinetics of TNF-alpha/IL-23 dual inhibitor and its corresponding liberated anti-TNF–alpha and anti-IL–23 monomer arms in fecal samples collected from individuals orally administered twice daily with 1215 mg TNF-alpha/IL-23 dual inhibitor.
  • FIGURE 6A shows arithmetic mean concentrations and individual data points. Only positive points were included in mean calculation and in the figure unless all data points for a given day were below the lower limit of quantification.
  • FIGURE 6B shows median concentrations and individual data points. Only positive points were included in mean calculation and in the figure unless all data points for a given day were below the lower limit of quantification.
  • the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed embodiments. [0021] As used herein the term “about” refers to an amount that is near the stated amount by 10% or less. [0022] As used herein the term “individual,” “patient,” or “subject” refers to individuals diagnosed with, suspected of being afflicted with, or at-risk of developing at least one disease for which the described compositions and method are useful for treating. In certain embodiments the individual is a mammal.
  • the mammal is a mouse, rat, rabbit, dog, cat, horse, cow, sheep, pig, goat, llama, alpaca, or yak.
  • the individual is a human.
  • “Treat,” “treatment,” or “treating,” as used herein refers to, e.g., a deliberate intervention to a physiological disease state resulting in the reduction in severity of a disease or condition; the reduction in the duration of a condition course; the amelioration or elimination of one or more symptoms associated with a disease or condition; the maintenance of a therapeutic benefit, or the provision of beneficial effects to a subject with a disease or condition. Treatment does not require curing the underlying disease or condition.
  • a “therapeutically effective amount”, “effective dose”, “effective amount”, or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • the ability of a therapeutic WSGR Docket No.60790-714.601 agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
  • polypeptide and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length.
  • Polypeptides including the provided antibodies and antibody chains and other peptides, e.g., linkers and binding peptides, may include amino acid residues including natural and/or non-natural amino acid residues.
  • the terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like.
  • the polypeptides may contain modifications with respect to a native or natural sequence, as long as the protein maintains the desired activity.
  • antibody herein is used in the broadest sense and includes monoclonal antibodies, bispecific antibodies, and includes intact antibodies and functional (antigen-binding) antibody fragments thereof, including fragment antigen binding (Fab) fragments, F(ab') 2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rIgG) fragments, single chain antibody fragments, including single chain variable fragments (sFv or scFv), VHHs, vorobodies, immunoglobulin chain variable domains, and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments.
  • Fab fragment antigen binding
  • F(ab') 2 fragments fragment antigen binding
  • Fab' fragments fragment antigen binding
  • Fv fragments fragment antigen binding fragments
  • rIgG recombinant IgG fragments
  • single chain antibody fragments including single chain variable fragments (sFv or scFv), VHHs, vorobodies, immuno
  • the term encompasses genetically engineered and/or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv.
  • antibody should be understood to encompass functional antibody fragments thereof.
  • the term also encompasses intact or full- length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD.
  • the antibody can comprise a human IgG1 constant region.
  • the antibody can comprise a human IgG4 constant region.
  • small molecule typically refer to organic, inorganic or organometallic compounds having a molecular weight of less than about 2000 Daltons.
  • pharmaceutically acceptable with reference to a carrier” “excipient” or “diluent” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
  • the active compound i.e., antibody
  • the active compound can be WSGR Docket No.60790-714.601 coated in a material to protect the compound from the action of acids and other natural conditions that can inactivate the compound.
  • the pharmaceutical compounds described herein can include one or more pharmaceutically acceptable salts.
  • a “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S.M., et al. (1977) J. Pharm. Sci.66: 1-19). Examples of such salts include acid addition salts and base addition salts.
  • Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
  • Percent (%) sequence identity with respect to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, 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. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are known for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code.
  • the ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • the “% WSGR Docket No.60790-714.601 sequence identity" between a first polypeptide sequence and a second polypeptide sequence may be calculated using NCBI BLAST v2.0, using standard settings for polypeptide sequences (BLASTP).
  • the “% sequence identity" between a first nucleotide sequence and a second nucleotide sequence may be calculated using NCBI BLAST v2.0, using standard settings for nucleotide sequences (BLASTN).
  • the BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
  • W wordlength
  • E expectation
  • the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc.
  • nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more suitably less than about 0.01, and most suitably less than about 0.001.
  • Polypeptide or polynucleotide sequences are said to be the same as or identical to other polypeptide or polynucleotide sequences, if they share 100% sequence identity over their entire length. Residues in sequences are numbered from left to right, i.e. from N- to C- terminus for polypeptides; from 5’ to 3’ terminus for polynucleotides. [0033] A “difference” between sequences refers to an insertion, deletion or substitution of at least a single amino acid residue in a position of the second sequence, compared to the first sequence. Two polypeptide sequences can contain one, two or more such amino acid differences.
  • Insertions, deletions or substitutions in a second sequence which is otherwise identical (100% sequence identity) to a first sequence result in reduced % sequence identity. For example, if the identical sequences are 9 amino acid residues long, one substitution in the second sequence results in a sequence identity of 88.9%. If the identical sequences are 17 amino acid residues long, two substitutions in the second sequence results in a sequence identity of 88.2%. If the identical sequences are 7 amino acid residues long, three substitutions in the second sequence results in a sequence identity of 57.1%.
  • first and second polypeptide sequences are 9 amino acid residues long and share 6 identical residues, the first and second polypeptide WSGR Docket No.60790-714.601 sequences share greater than 66% identity (the first and second polypeptide sequences share 66.7% identity). If first and second polypeptide sequences are 17 amino acid residues long and share 16 identical residues, the first and second polypeptide sequences share greater than 94% identity (the first and second polypeptide sequences share 94.1% identity). If first and second polypeptide sequences are 7 amino acid residues long and share 3 identical residues, the first and second polypeptide sequences share greater than 42% identity (the first and second polypeptide sequences share 42.9% identity).
  • the number of additions, substitutions and/or deletions made to the first sequence to produce the second sequence may be ascertained.
  • An addition is the addition of one amino acid residue into the sequence of the first polypeptide (including addition at either terminus of the first polypeptide).
  • a substitution is the substitution of one amino acid residue in the sequence of the first polypeptide with one different amino acid residue.
  • a deletion is the deletion of one amino acid residue from the sequence of the first polypeptide (including deletion at either terminus of the first polypeptide).
  • the number of additions, substitutions and/or deletions made to the first sequence to produce the second sequence may be ascertained.
  • An addition is the addition of one nucleotide residue into the sequence of the first polynucleotide (including addition at either terminus of the first polynucleotide).
  • a substitution is the substitution of one nucleotide residue in the sequence of the first polynucleotide with one different nucleotide residue.
  • a deletion is the deletion of one nucleotide residue from the sequence of the first polynucleotide (including deletion at either terminus of the first polynucleotide).
  • Antibodies and antibody-derived binding moieties [0037] The antibodies or antibody-derived binding moieties described herein can be encoded by a nucleic acid.
  • a nucleic acid is a type of polynucleotide comprising two or more nucleotide bases.
  • the nucleic acid is a component of a vector that can be used to transfer the polypeptide encoding polynucleotide into a cell.
  • vector refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has WSGR Docket No.60790-714.601 been linked.
  • Immunoglobulin chain variable domains of the invention may, for example, be obtained by preparing a nucleic acid encoding an immunoglobulin chain variable domain using techniques for nucleic acid synthesis, followed by expression of the nucleic acid thus obtained. [0038] Among the provided antibodies are antibody fragments.
  • antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
  • antibody fragments include, but are not limited to, Fv, Fab, Fab’, Fab’-SH, F(ab’)2 ; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv or sFv); and multispecific antibodies formed from antibody fragments.
  • the antibodies are single-chain antibody fragments comprising a variable heavy chain region and/or a variable light chain region, such as scFvs or single heavy chain variable domains.
  • a molecule, peptide, polypeptide, antibody, or antibody fragment can be referred to as “bispecific” or “dual-specific” including grammatical equivalents.
  • a bispecific molecule possesses the ability to specifically bind to at least two structurally distinct targets.
  • the specific binding may be the result of two distinct binding moieties that are structurally distinct at the molecular level, including but not limited to distinct non-identical amino acid sequences; or a single binding moiety that is able to specifically bind to two structurally distinct targets with high affinity (e.g., with a dissociation constant (K D ) less than about 1x10 -6 ).
  • K D dissociation constant
  • a molecule, peptide, polypeptide, antibody, or antibody fragment referred to as “multi-specific” refers to a molecule that possesses the ability to specifically bind to at least three structurally distinct targets.
  • a “bispecific antibody” including grammatical equivalents refers to a bispecific molecule that preserves at least one fragment of an antibody able to specifically bind a target, for example, a variable region, heavy or light chain, or one or more complementarity determining regions from an antibody molecule.
  • a “multi-specific antibody” including grammatical equivalents refers to a multi-specific molecule that preserves at least one fragment of an antibody able to specifically bind with a target, for example, a variable region, heavy or light chain, or complementarity determining region from an antibody molecule.
  • a “linker” herein is also referred to as “linker sequence” “spacer” “tethering sequence” or grammatical equivalents thereof.
  • a “linker” as referred herein connects two distinct molecules that by themselves possess target binding, catalytic activity, or are naturally expressed and assembled as separate polypeptides, or comprise separate domains of the same polypeptide. For example, two distinct binding moieties or a heavy-chain/light-chain pair.
  • Linkers described herein may be utilized to join a light chain variable region and a heavy chain variable region in WSGR Docket No.60790-714.601 an scFv molecule; or may be used to tether an scFv or other antigen binding fragment on the N- or C- terminus of an antibody heavy chain; or the N- or C- terminus of a light chain to create a bispecific or multispecific binding molecule.
  • These include but are not limited to polypeptide linkages between N- and C-termini of proteins or protein domains, linkage via disulfide bonds, and linkage via chemical cross-linking reagents.
  • the linker is a peptide bond, generated by recombinant techniques or peptide synthesis.
  • the linker peptide may predominantly include the following amino acid residues: Gly, Ser, Ala, or Thr.
  • the linker peptide should have a length that is adequate to link two molecules in such a way that they assume the correct conformation relative to one another so that they retain the desired activity.
  • the linker is from about 1 to 50 amino acids in length, or about 1 to 30 amino acids in length. In one embodiment, linkers of 1 to 20 amino acids in length may be used.
  • Useful linkers include glycine-serine polymers, including for example (GS)n, (GSGGS)n (SEQ ID NO: 303), (GGGGS)n (SEQ ID NO: 304), and (GGGS)n (SEQ ID NO: 305), where n is an integer of at least one, glycine-alanine polymers, alanine-serine polymers, and other flexible linkers.
  • linkers for linking antibody fragments, single chain variable fragments, or VHHs can include AAEPKSS (SEQ ID NO: 306), AAEPKSSDKTHTCPPCP (SEQ ID NO: 307), GGGG (SEQ ID NO: 308), or GGGGDKTHTCPPCP (SEQ ID NO: 309).
  • AAEPKSS SEQ ID NO: 306
  • AAEPKSSDKTHTCPPCP SEQ ID NO: 307
  • GGGG SEQ ID NO: 308
  • GGGGDKTHTCPPCP SEQ ID NO: 309
  • a variety of non-proteinaceous polymers including but not limited to polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, may find use as linkers.
  • the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 301 (GGGGSKGGGGS).
  • the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 302 (GGGGSGGGGSKGGGGSGGGGS).
  • CDR complementarity determining region
  • HVR hypervariable region
  • the CDRs of the antibodies described herein can be defined by a method selected from Kabat, Chothia, IMGT, Aho, AbM, or combinations thereof.
  • the boundaries of a given CDR or FR may vary depending on the scheme used for identification.
  • the Kabat scheme is based on structural alignments
  • the Chothia scheme is based on structural information.
  • Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertions accommodated by insertion letters, for example, “30a,” and deletions appearing in some antibodies. The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering.
  • the Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme.
  • Specific binding or binding of antibody molecules described herein refers to binding mediated by one or more CDR portions of the antibody. Not all CDRs may be required for specific binding. Specific binding can be demonstrated for example by an ELISA against a specific recited target or antigen that shows significant increase in binding compared to an isotype control antibody.
  • the term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen.
  • variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs (See e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91(2007)).
  • FRs conserved framework regions
  • CDRs See e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91(2007)).
  • a single VH or VL domain may be sufficient to confer antigen-binding specificity.
  • antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary V L or V H domains, WSGR Docket No.60790-714.601 respectively (See e.g., Portolano et al., J. Immunol.150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).
  • Substituting at least one amino acid residue in the framework region of a non-human immunoglobulin variable domain with the corresponding residue from a human variable domain is humanization. Humanization of a variable domain may reduce immunogenicity in humans.
  • IgG antibodies are devoid of the L chain polypeptide and lack the first constant domain (CH1).
  • VHHs are single-domain antibodies that comprise a single heavy chain variable domain.
  • VHHs Similar to the variable domains from conventional antibodies, VHHs comprise four FRs and three CDRs ( Figure 1A). Unlike conventional antibodies, VHHs do not have nor require a light chain variable domain to pair with its heavy chain variable domain for antigen binding to occur.
  • the VHHs described herein are stable throughout recombinant production and in vivo delivery.
  • the VHHs described herein are resistant to cleavage by recombinant host organism (e.g., yeast) proteases and by proteases present in the GI tract.
  • the total number of amino acid residues in a VHH or VH may be in the region of 110-130.
  • VHHs can be used to construct multivalent and/or multispecific polypeptides.
  • a polypeptide described herein can comprise at least two identical VHHs ( Figure 1B).
  • a polypeptide described herein can comprise at least two distinct VHHs ( Figure 1C).
  • a multivalent polypeptide comprises two or more binding polypeptides (e.g., VHHs) which presents two or more sites at which binding to one or more antigens can occur.
  • a multispecific polypeptide comprises two or more distinct binding polypeptides (e.g., VHHs) which present two or more sites at which either (a) binding to two or more distinct antigens can occur or (b) binding to two or more distinct epitopes on the same antigen can occur.
  • VHHs distinct binding polypeptides
  • Multivalent and/or multispecific polypeptides described herein can incorporate WSGR Docket No.60790-714.601 linkers to covalently join functional domains (e.g., VHHs) together to act as one molecule throughout the recombinant production process and/or in vivo delivery.
  • the linkers described herein can be stable and resistant to cleavage by recombinant host organism (e.g., yeast) proteases as well as proteases present in the GI tract.
  • the linkers described herein can be labile.
  • the labile peptide linker can be engineered such that it resists cleavage by proteases to a desired extent and/or is only cleaved upon exposure to a specific area of the intestinal tract. This can be achieved according to one embodiment of the invention by incorporating shielding residues into the labile peptide linker flanking the labile site(s).
  • Shielding residues flank the labile site(s) of the labile peptide linker and reduce the lability thereof. Cleavage resistance can also be increased by positioning the labile site(s) closer to or at the periphery of the labile peptide linker. This concept is referred to as a “shielded labile site” and provides controlled lability.
  • the labile peptide linker can be engineered such that it is highly labile to cleavage by intestinal tract proteases, thereby quickly releasing the constituent first and second polypeptides of the construct after oral administration.
  • the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 301 (GGGGSKGGGGS). In certain embodiments, the linker comprises or consists of the amino acid sequence set forth in SEQ ID NO: 302 (GGGGSGGGGSKGGGGSGGGGS).
  • Specificity refers to the number of different types of antigens or antigenic determinants to which a particular antigen-binding polypeptide can bind.
  • the specificity of an antigen-binding polypeptide is the ability of the antigen-binding polypeptide to recognize a particular antigen as a unique molecular entity and distinguish it from another.
  • Affinity represented by the equilibrium constant for the dissociation of an antigen with an antigen-binding polypeptide (KD) is a measure of the binding strength between an antigenic determinant and an antigen-binding site on the antigen-binding polypeptide: the lesser the value of the K D , the stronger the binding strength between an antigenic determinant and the antigen-binding polypeptide (alternatively, the affinity can also be expressed as the affinity constant (Ka), which is 1/ KD).
  • affinity can be determined by known methods, depending on the WSGR Docket No.60790-714.601 specific antigen of interest.
  • affinity is determined using a dynamically switchable biosurface (e.g.
  • Avidity is the measure of the strength of binding between an antigen-binding polypeptide and the pertinent antigen. Avidity is related to both the affinity between an antigenic determinant and its antigen binding site on the antigen-binding polypeptide and the number of pertinent binding sites present on the antigen-binding polypeptide.
  • an antibody or antibody-derived binding moiety provided herein has a K D nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM, or 1 pM or less (e.g., 10 M or less, e.g., from 10 M to 10 M, e.g., from 10 M to 10 M) for the antibody target.
  • an antibody or antibody-derived binding moiety provided herein has a KD of about 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM, or 1 pM or greater (e.g., 10 M or greater, e.g., from 10 M to 10 M, e.g., from 10 M to 10 M) for the antibody target.
  • K D can be measured by any suitable assay.
  • K D can be measured using surface plasmon resonance assays (e.g., using a BIACORE®-2000, a BIACORE®-3000 or Octet).
  • the antibody or antibody-derived binding moiety can be an IL-23 or an IL-23 receptor targeting antibody or VHH.
  • the IL-23–specific polypeptide of the invention can bind to IL-23 with a KD of 10 M or less, 10 -7 M or less, 10 -8 M or less, 10 -9 M or less, 10 -10 M or less, 10 -11 M or less, 10 -12 M or less, or 10 -13 M or less.
  • the polypeptide of the invention can bind to IL-23 with a KD of 10 M or greater, 10 -7 M or greater, 10 -8 M or greater, 10 -9 M or greater, 10 -10 M or greater, 10 -11 M or greater, 10- 12 M or greater, or 10 -13 M or greater. In some embodiments, the polypeptide of the invention can bind to IL-23 with a K D of 10 M to 10 M, 10 -7 to 10 -13 M, 10 -8 to 10 -13 M, or 10 -9 to 10 -13 M.
  • the antibody or antibody-derived binding moiety can be a TNF-alpha or a TNF receptor targeting antibody or VHH.
  • the polypeptide of the invention can bind to TNF-alpha with a K D of 10 M or less, 10 -7 M or less, 10 -8 M or less, 10 -9 M or less, 10- 10 M or less, 10 -11 M or less, 10 -12 M or less, or 10 -13 M or less. In some embodiments, the polypeptide of the invention can bind to TNF-alpha with a KD of 10 M or greater, 10 -7 M or greater, 10 -8 M or greater, 10 -9 M or greater, 10 -10 M or greater, 10 -11 M or greater, 10 -12 M or greater, or 10 -13 M or greater.
  • the polypeptide of the invention can bind to TNF-alpha with a KD of 10 M to 10 M, 10 -7 to 10 -13 M, 10 -8 to 10 -13 M, or 10 -9 to 10 -13 M.
  • a K D value less than 10 -6 M can be considered to indicate binding.
  • Specific binding WSGR Docket No.60790-714.601 of an antigen-binding polypeptide to an antigen or antigenic determinant can be determined in any suitable known manner, including, for example, Scatchard analysis and/or competitive binding assays, surface plasmon resonance such as radioimmunoassays (RIA), enzyme immunoassays (EIA) and sandwich competition assays, and the different variants thereof known in the art.
  • Stability [0057]
  • the polypeptide or construct of the present invention substantially retains neutralization ability and/or potency when delivered orally and after exposure to the intestinal tract (for example, after exposure to proteases of the small and/or large intestine and/or IBD inflammatory proteases).
  • proteases include enteropeptidase, trypsin, chymotrypsin, and irritable bowel disease inflammatory proteases (such as MMP3, MMP12 and cathepsin).
  • proteases include enteropeptidase, trypsin, chymotrypsin, and irritable bowel disease inflammatory proteases (such as MMP3, MMP12 and cathepsin).
  • proteases sourced from intestinal commensal microflora and/or pathogenic bacteria, for example wherein the proteases are cell membrane-attached proteases, excreted proteases and proteases released on cell lysis).
  • the proteases are trypsin and chymotrypsin.
  • the gastrointestinal tract comprises the mouth, pharynx, esophagus, stomach, small intestine, large intestine, rectum, and anus.
  • the gastrointestinal tract is the gastrointestinal tract of a dog, pig, human, cynomolgus monkey or mouse.
  • the intestinal tract is the intestinal tract of a dog, pig, human, cynomolgus monkey or mouse.
  • the small intestine can consist of the duodenum, jejunum and ileum.
  • the large intestine can consist of the cecum, colon, rectum and anal canal.
  • the intestinal tract can consist of only the small intestine and the large intestine.
  • the polypeptide or construct of the invention substantially retains neutralization ability after exposure to proteases present in the small and/or large intestine and/or IBD inflammatory proteases for, for example, up to at least 1, more suitably up to at least 2, more suitably up to at least 3, more suitably up to at least 4, more suitably up to at least 7, more suitably up to at least 16 hours at 37 o C.
  • proteases present in the small and/or large intestine and/or IBD inflammatory proteases for, for example, up to at least 1, more suitably up to at least 2, more suitably up to at least 3, more suitably up to at least 4, more suitably up to at least 7, more suitably up to at least 16 hours at 37 o C.
  • Autoimmune and/or inflammatory diseases [0060] Autoimmune diseases develop when the immune system responds adversely to normal body tissues.
  • Autoimmune disorders may result in damage to body tissues, abnormal WSGR Docket No.60790-714.601 organ growth and/or changes in organ function.
  • the disorder may affect only one organ or tissue type or may affect multiple organs and tissues.
  • Organs and tissues commonly affected by autoimmune disorders include blood components such as red blood cells, blood vessels, connective tissues, endocrine glands such as the thyroid or pancreas, muscles, joints and skin
  • An inflammatory disease is a disease characterized by inflammation. Many inflammatory diseases are autoimmune diseases and vice-versa.
  • a non-limiting list of other autoimmune and inflammatory diseases afflicting the GI tract include GI cancers, colitis, microscopic colitis, celiac disease, mucositis, pouchitis, or gastritis.
  • a non-limiting list of GI cancers include anal cancer, bile duct cancer, colon cancer, esophageal cancer, small intestine cancer, and gastric cancer.
  • the chronic inflammatory bowel diseases, Crohn’s disease and ulcerative colitis are examples of autoimmune and inflammatory diseases of the GI tract (Hendrickson et al.2002 Clin Microbiol Rev 15(1):79-94, herein incorporated by reference in its entirety).
  • Ulcerative colitis is a condition where the inflammatory response and morphologic changes remain confined to the colon. The rectum is involved in 95% of patients. Inflammation is largely limited to the mucosa and consists of continuous involvement of variable severity with ulceration, edema, and hemorrhage along the length of the colon (Hendrickson et al.2002 Clin. Microbiol Rev 15(1):79-94, herein incorporated by reference in its entirety). Ulcerative colitis is a presently incurable life-long GI disease, and is usually manifested by the presence of blood and mucus mixed with stool, along with lower abdominal cramping which is most severe during the passage of bowel movements.
  • Crohn’s disease also known as Crohn disease, Crohn syndrome and regional enteritis, is a type of inflammatory bowel disease causing a wide variety of symptoms. It primarily causes abdominal pain, diarrhea, vomiting and/or weight loss but may also cause complications outside GI tract such as anemia, skin rashes, arthritis, inflammation of the eye, tiredness, and lack of concentration (Baumgart et al.2012 The Lancet 380(9853):1590–605, herein incorporated by reference in its entirety).
  • Crohn’s disease is a presently incurable life- long GI disease that can affect any portion of the GI tract, and is difficult to control with conventional therapies. Unlike ulcerative colitis, the presentation of Crohn’s disease is usually subtle, which leads to a later diagnosis. Factors such as the location, extent, and severity of WSGR Docket No.60790-714.601 involvement determine the extent of GI symptoms. Patients who have ileocolonic involvement usually have postprandial abdominal pain, with tenderness in the right lower quadrant and an occasional inflammatory mass. Symptoms associated with gastroduodenal Crohn’s disease include early satiety, nausea, emesis, epigastric pain, or dysphagia.
  • Perianal disease is common, along with anal tags, deep anal fissures, and fistulae (Hendrickson et al.2002 Clin Microbiol Rev 15(1):79-94, herein incorporated by reference in its entirety).
  • TNF-alpha and IL-23 in autoimmune diseases and/or inflammatory diseases are characterized by aberrant activation of pro-inflammatory pathways. While the root pathology of autoimmune and/or inflammatory diseases remain to be fully elucidated, therapeutic strategies that aim to dampen pro- inflammatory pathways can provide sustained relief or induce remission to patients suffering from autoimmune and/or inflammatory diseases.
  • TNF-alpha (UniProt ID: P01375, www.uniprot.org/uniprotkb/P01375/entry) is a pleiotropic cytokine that is involved in a variety of pro-inflammatory cellular processes and is also implicated in the pathogenesis of autoimmune and/or inflammatory diseases.
  • TNF alpha is a homo-trimeric protein that is primarily secreted by immune cell types, including natural killer (NK) cells, T cells, macrophages, and monocytes; and TNF-alpha can also be expressed as a transmembrane protein.
  • NK natural killer
  • TNFR1 tumor necrosis factor receptor 1
  • TNFR2 tumor necrosis factor receptor 2
  • MAPK nuclear factor kappa-
  • IL-23 is a heterodimeric pro-inflammatory cytokine, comprising an IL-23A subunit (also known as IL-23p19; UniProt ID: Q9NPF7, www.uniprot.org/uniprotkb/Q9NPF7/entry) that shares an IL-12B subunit (also known as IL-12/23p40, UniProt ID: P29460, www.uniprot.org/uniprotkb/P29460/entry) with IL-12, that is implicated in the pathogenesis of autoimmune and/or inflammatory diseases.
  • IL-23A subunit also known as IL-23p19; UniProt ID: Q9NPF7, www.uniprot.org/uniprotkb/Q9NPF7/entry
  • IL-12B subunit also known as IL-12/23p40, UniProt ID: P29460, www.uniprot.org/uniprotkb/P29460
  • IL-23 is primarily secreted by immune cell types, such as activated macrophages, monocytes, or dendritic cells (DCs), can promote recruitment and activation of immune cells, such as macrophages and granulocytes, and is implicated in the maintenance and expansion of a pro-inflammatory T helper 17 (Th17) cells.
  • IL-23 signaling is mediated by binding of the IL-23A subunit (also known as IL-23p19) to the IL-23 receptor (IL- mediated signal transducer and activator of transcription (STAT) signaling.
  • IL-23A subunit also known as IL-23p19
  • STAT IL- mediated signal transducer and activator of transcription
  • IL-23 WSGR Docket No.60790-714.601 binding can recruit of JAK2 and TYK2 for the induction of STAT3 and/or STAT4 signaling pathways.
  • Inhibitors of IL-23 [0066] Inhibitors of IL-23 described herein can antagonize IL-23–induced cellular processes, which include pro-inflammatory pathways. In some embodiments, inhibitors of IL-23 described herein binds to human IL-23.
  • inhibitors of IL-23 described herein can bind to both human and at least one additional primate IL-23 selected from the group consisting of baboon IL-23, marmoset IL-23, cynomolgus IL-23, and rhesus IL-23.
  • inhibitors of IL-23 described herein can bind to the IL-23A subunit (also known as IL-23p19) of IL-23.
  • inhibitors of IL-23 described herein may bind to a linear or conformational epitope on IL-23.
  • inhibitors of IL-23 described herein can bind to IL-23R.
  • inhibitors of IL-23 described herein can block binding of the IL-23A subunit to IL-23R. In some embodiments, inhibitors of IL-23 described herein can block binding of IL-23 to IL-23R. In some embodiments, inhibitors of IL-23 described herein can bind to the IL-12B subunit (also known as IL-12/23p40) of IL-23.
  • inhibitors of IL-23 described herein can block binding of IL-23 to IL- [0067] In some embodiments, inhibitors of IL-23 described herein can be directed against epitopes on IL-23 that lie in and/or form part of the receptor binding site(s) of IL-23, such that said inhibitors of IL-23, upon binding to IL-23, is capable inhibiting or reducing the IL-23 receptor crosslinking that is mediated by said IL-23 and/or the signal transduction that is mediated by such receptor crosslinking. [0068] In some embodiments, inhibitors of IL-23 described herein can block signaling pathways activated in response to IL-12.
  • inhibitors of IL-23 described herein can block signaling pathways activated in response to IL-23. In some embodiments, inhibitors of IL-23 described herein can inhibit JAK/STAT signaling. In some embodiments, inhibitors of IL-23 described herein can inhibit STAT3 signaling, STAT4 signaling, or combinations thereof. In some embodiments, inhibitors of IL-23 described herein can inhibit cellular processes downstream of STAT3 signaling, STAT4 signaling, or combinations thereof. In some embodiments, inhibitors of IL-23 described herein can inhibit expression of pro- WSGR Docket No.60790-714.601 inflammatory genes.
  • the inhibitor of IL-23 comprises an antibody that binds IL-23 or an IL-23 binding fragment thereof.
  • the antibody that binds IL-23 or an IL-23 binding fragment thereof comprises risankizumab, guselkumab, tildrakizumab, briakinumab, brazikumab, mirikizumab, ustekinumab, or combinations thereof.
  • the antibody that binds to IL-23 or an IL-23 binding fragment thereof comprises a VHH.
  • the IL-23 binding VHH comprises: a) a CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 4, or 7; b) a CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 5, or 8; and c) a CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 3, 6, or 9.
  • the IL-23 binding VHH comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NOs: 10-12.
  • inhibitors of IL-23 described herein can bind to one or more epitope(s) on IL-23.
  • an inhibitor of IL-23 which binds to the same epitope on IL-23 as ID-L253T, 12G1, 1E2, 10E2 or 10G10.
  • Inhibitors of TNF-alpha [0072] Inhibitors of TNF-alpha described herein can antagonize TNF-alpha–induced cellular processes, including pro-inflammatory pathways. In some embodiments, inhibitors of TNF- alpha described herein can bind to the soluble form of TNF-alpha.
  • inhibitors of TNF-alpha described herein can bind to transmembrane forms of TNF-alpha. In some embodiments, inhibitors of TNF-alpha described herein can bind to both soluble forms of TNF-alpha, transmembrane forms of TNF-alpha, or combinations thereof. In some embodiments, inhibitors of TNF-alpha described herein can also bind to TNFR1. In some embodiments, inhibitors of TNF-alpha described herein can also bind to TNFR2. In some embodiments, inhibitors of TNF-alpha described herein can also bind to TNFR1, TNFR2, or combinations thereof.
  • inhibitors of TNF-alpha described herein can bind to both soluble and transmembrane forms of TNF-alpha. In some embodiments, inhibitors of TNF-alpha described herein can block binding of the soluble form of TNF-alpha to TNFR1. In some embodiments, inhibitors of TNF-alpha described herein can block binding of the soluble form of TNF-alpha to TNFR2. In some embodiments, inhibitors of TNF-alpha described herein can block binding of the transmembrane form of TNF-alpha to TNFR1.
  • inhibitors of TNF-alpha described herein can block binding of the transmembrane form of TNF- WSGR Docket No.60790-714.601 alpha to TNFR2. In some embodiments, inhibitors of TNF-alpha described herein can block binding of both the soluble and transmembrane form of TNF-alpha to TNFR1. In some embodiments, inhibitors of TNF-alpha described herein can block binding of both the soluble and transmembrane form of TNF-alpha to TNFR2. In some embodiments, inhibitors of TNF- alpha described herein can block binding of both the soluble and transmembrane form of TNF- alpha to TNFR1, TNRFR2, or combinations thereof.
  • inhibitors of TNF-alpha described herein can be directed against epitopes on TNF-alpha that lie in and/or form part of the receptor binding site(s) of TNF- alpha, such that said inhibitors of TNF-alpha, upon binding to TNF-alpha, is capable inhibiting or reducing the TNF-alpha receptor crosslinking that is mediated by said TNF-alpha and/or the signal transduction that is mediated by such receptor crosslinking.
  • inhibitors of TNF-alpha described herein can block signaling pathways activated in response to and/or MAPK signaling.
  • inhibitors of TNF-alpha described herein can inhibitors of TNF-alpha described herein can inhibit expression of pro-inflammatory genes.
  • the inhibitor of TNF-alpha comprises an antibody that binds TNF-alpha or a TNF-alpha binding fragment thereof.
  • the antibody that binds TNF-alpha or TNF-alpha binding fragment thereof comprises infliximab, adalimumab, certolizumab pegol, golimumab, or combinations thereof.
  • the inhibitor of TNF-alpha comprises a soluble TNF-alpha receptor.
  • the soluble TNF- alpha receptor can comprise etanercept.
  • the antibody that binds to TNF-alpha or a TNF-alpha binding fragment thereof comprises a VHH.
  • the TNF-alpha binding VHH comprises: a) a CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 101, 107, 108, or 119; b) a CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 102, 109-117, or 120; and c) a CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 103-106 or 121-124.
  • the TNF- alpha binding VHH comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NOs: 118 or 125.
  • Dual inhibitors of IL-23 and TNF-alpha [0076] Inhibitors described here can be an inhibitor of both IL-23 and TNF-alpha.
  • the inhibitor of IL-23 and TNF-alpha can comprise an antibody that binds IL-23 WSGR Docket No.60790-714.601 and an IL-23 binding fragment thereof.
  • the inhibitor of IL-23 and TNF- alpha can comprise an antibody that binds TNF-alpha and a TNF-alpha binding fragment thereof. In some embodiments, the inhibitor of IL-23 and TNF-alpha can comprise an antibody that binds IL-23, an IL-23 binding fragment thereof, an antibody that binds TNF-alpha, a TNF- alpha binding fragment thereof, or combinations thereof. In some embodiments, the inhibitor of IL-23 and TNF-alpha can comprise a covalent fusion of an inhibitor of IL-23 and an inhibitor of TNF-alpha. In some embodiments, the inhibitor of IL-23 and TNF-alpha can comprise a peptide linker.
  • the inhibitor of IL-23 and TNF-alpha comprises a combination therapeutic that is a co-formulated composition comprising an IL-23 and a TNF- alpha inhibitor.
  • the inhibitor of IL-23 and TNF-alpha comprises a polypeptide that binds to IL-23 and TNF-alpha (e.g., an IL-23 and TNF-alpha bispecific antibody).
  • the polypeptide that binds to IL-23 and TNF-alpha comprises a first binding region that binds to TNF-alpha and a second binding region that binds to TNF- alpha
  • the first binding region that binds TNF-alpha comprises: a) a CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 101, 107, 108, or 119; b) a CDR2 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 102, 109- 117, or 120; and c) a CDR3 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 103-106 or 121-124;
  • the second binding region that binds IL-23 comprises: a) a CDR1 comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 4, or 7; b) a CDR2 comprising an amino acid sequence as set forth
  • the first binding region that binds TNF-alpha comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID 118 or 125; and the second binding region that binds IL-23 comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in any one of SEQ ID NOs: 10-12.
  • the first binding region and the second binding region are coupled by a linker.
  • the first binding region and the second binding region are coupled by a protease-labile linker.
  • the inhibitor of IL-23 and TNF-alpha comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 201. In some embodiments, the inhibitor of IL-23 and TNF-alpha comprises an amino acid sequence at least about 85%, 90%, 95%, 97%, 98%, or 99% identical to that set forth in SEQ ID NO: 202.
  • the autoimmune or inflammatory condition of the GI tract comprises IBD. In some embodiments, the autoimmune or inflammatory condition of the GI tract comprises Crohn’s disease, ulcerative colitis, colitis, microscopic colitis, celiac disease, mucositis, pouchitis, or gastritis. In some embodiments, the autoimmune or inflammatory condition of the GI tract is Crohn’s disease. In some embodiments, the autoimmune or inflammatory condition of the GI tract is ulcerative colitis.
  • Administration route [0079] The methods of treatment described herein can encompass systemic administration. The methods of treatment described herein can encompass local administration.
  • the local administration is oral administration of a polypeptide, immunoglobulin, or VHH that does not achieve systemic availability by an oral route.
  • the methods of treatment described herein can be administered to an individual in need thereof through parenteral administration or enteral administration.
  • the enteral administration route encompasses administration involving the GI tract.
  • enteral administration encompasses administration to the alimentary canal.
  • Non-limiting examples of enteral administration include oral administration, rectal administration, or direct administration to the alimentary canal or a portion thereof.
  • enteral administration can be provided as a suppository.
  • enteral administration is oral administration.
  • enteral administration is administered by gavage or intubation.
  • enteral administration can be provided orally as a liquid, as a nutraceutical, or as a powder. In some embodiments, enteral administration can be provided orally in the form of a pill. In some embodiments, enteral administration can be provided orally to a specified area of G.I. tract in the form of a capsule. In some embodiments, enteral administration can be provided orally to the colon in the form of a capsule. In contrast, the parenteral administration route encompasses any administration route that is not enteral. In some instances, parenteral administration can be achieved through needle injection or administration through an implanted catheter.
  • parenteral administration include intramuscular, subcutaneous, intravenous, intradermal, intrathecal, nasal, intraocular, and inhalation administration.
  • WSGR Docket No.60790-714.601 the parenteral administration route is subcutaneous administration.
  • the parenteral administration route is intravenous administration.
  • parenteral administration can enable systemic delivery of the therapeutic.
  • parenteral administration can enable local delivery of the therapeutic.
  • enteral administration can enable systemic delivery of the therapeutic.
  • enteral administration can enable local delivery of the therapeutic.
  • a pharmaceutical composition of the invention may suitably be formulated for oral, intramuscular, subcutaneous or intravenous delivery.
  • compositions of the invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. In some embodiments, solid dosage forms are preferred.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions e.g., injectable and infusible solutions
  • tablets e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • solid dosage forms are preferred.
  • the inhibitors of IL-23 and TNF-alpha described herein may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the pharmaceutical composition comprises a polypeptide or construct that is an inhibitor of IL-23 and TNF-alpha, and a pharmaceutically acceptable excipient, diluent, or carrier.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the polypeptide or construct of the invention.
  • compositions may include antiadherents, binders, coatings, disintegrants, flavors, colors, lubricants, sorbents, preservatives, sweeteners, freeze dry excipients (including lyoprotectants) or compression aids.
  • the inhibitors of IL-23 and TNF-alpha described herein is administered orally.
  • a key problem with oral delivery is ensuring that a sufficient amount of the inhibitors of IL-23 and TNF-alpha reach the area of the intestinal tract where it is required.
  • Factors which may prevent inhibitors of IL-23 and TNF-alpha of the invention from reaching the area of the intestinal tract where it is required may include the presence of proteases in digestive secretions which may degrade a polypeptide, pharmaceutical composition or construct of the invention.
  • the inhibitors of IL-23 and TNF-alpha described herein are substantially stable in the presence of one or more of such proteases by virtue of the inherent properties of the inhibitors of IL-23 and TNF-alpha itself.
  • the inhibitors of IL-23 and TNF- WSGR Docket No.60790-714.601 alpha described herein can be lyophilized before being incorporated into a pharmaceutical composition.
  • Suitable enteric coating components include methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, sodium alginate and stearic acid.
  • Suitable enteric coatings include pH-dependent release polymers. These are polymers which are insoluble at the highly acidic pH found in the stomach, but which dissolve rapidly at a less acidic pH.
  • the enteric coating will not dissolve in the acidic juices of the stomach (pH ⁇ 3), but will do so in the higher pH environment present in the small intestine (pH above 6) or in the colon (pH above 7.0).
  • the pH-dependent release polymer is selected such that the polypeptide or construct of the invention will be released at about the time that the dosage reaches the small intestine.
  • a lyoprotectant may also be added in order to protect the polypeptide or construct of the invention against destabilizing conditions during the lyophilization process.
  • lyoprotectants include sugars (including glucose, sucrose, mannose and trehalose); polyols (including mannitol, sorbitol and glycerol); and amino acids (including alanine, glycine and glutamic acid). Lyoprotectants can be included in an amount of about 10 mM to 500 mM.
  • Therapeutic dosage can impact the efficacy and durability in disease treatment. The therapeutic dosage can be defined through several metrics. In some instances, therapeutic dosage can by mass (e.g., mg). In some instances, therapeutic dosage can be defined by mass normalized to the weight of an individual in need thereof (e.g., mg/kg).
  • therapeutic dosage can be defined by mass normalized to the height of an individual in need thereof (e.g., mg/m). In some instances, therapeutic dosage can be defined by mass normalized to the body surface area of an individual in need thereof (e.g., mg/m 2 ). [0086]
  • the dosage ranges for administration of the inhibitors of IL-23 and TNF-alpha described herein are those to produce the desired therapeutic effect.
  • the dosage range required depends on the precise nature of the inhibitor of IL-23 and TNF-alpha, the route of administration, the nature of the formulation, the age of the patient, the weight, height and body WSGR Docket No.60790-714.601 surface are of the patient, the nature, extent or severity of the patient's condition, contraindications, if any, and the judgement of the attending physician. Variations in these dosage levels can be adjusted using standard empirical routines for optimization.
  • the therapeutic can be an inhibitor of IL-23, an inhibitor of TNF-alpha, or an inhibitor of both IL-23 and TNF-alpha. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 100 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 135 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 270 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 405 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 540 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 675 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 810 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 945 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1,080 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1,215 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1,350 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2,025 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2,700 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 3,645 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 5,400 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 6,750 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 8,100 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 10,935 mg. [0088] In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 100 mg to about 10,935 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 100 mg to about 135 mg, about 100 mg to about 270 mg, about 100 mg to about 405 mg, about 100 mg to about 540 mg, about 100 mg to about 675 mg, about 100 mg to about 1,215 mg, about 100 mg to about 2,700 mg, about 100 mg to about 3,645 mg, about 100 mg to about 6,750 mg, about 100 mg to about WSGR Docket No.60790-714.601 8,100 mg, about 100 mg to about 10,935 mg, about 135 mg to about 270 mg, about 135 mg to about 405 mg, about 135 mg to about 540 mg, about 135 mg to about 675 mg, about 135 mg to about 1,215 mg, about 135 mg to about 2,700 mg, about 135 mg to about 3,645 mg, about 135 mg to about 6,750 mg, about 135 mg to about 8,100 mg, about 135 mg to about 10,935 mg, about 270 mg to about 405 mg, about 100 mg to about
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 100 mg, about 135 mg, about 270 mg, about 405 mg, about 540 mg, about 675 mg, about 1,215 mg, about 2,700 mg, about 3,645 mg, about 6,750 mg, about 8,100 mg, or about 10,935 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 100 mg, about 135 mg, about 270 mg, about 405 mg, about 540 mg, about 675 mg, about 1,215 mg, about 2,700 mg, about 3,645 mg, about 6,750 mg, or about 8,100 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 135 mg, about 270 mg, about 405 mg, about 540 mg, about 675 mg, about 1,215 mg, about 2,700 mg, about 3,645 mg, about 6,750 mg, about 8,100 mg, or about 10,935 mg. [0089] In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 100 mg to about 2,500 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 100 mg to about 1,200 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha WSGR Docket No.60790-714.601 is about 150 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 200 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 250 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 1,200 mg. about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 350 mg to about 1,200 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 400 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 450 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 500 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 550 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 600 mg to about 1,200 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 650 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 700 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 750 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 800 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 850 mg to about 1,200 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 900 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 950 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1,000 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1,050 mg to about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1,100 mg to about 1,200 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1,150 mg to about 1,200 mg. [0090] In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 100 mg to about 2,500 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 1,200 mg. In WSGR Docket No.60790-714.601 some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 1,150 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 1,100 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 1,050 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 1,000 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 950 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL- 23 and TNF-alpha is about 300 mg to about 900 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 850 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 800 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 750 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 700 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL- 23 and TNF-alpha is about 300 mg to about 650 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 600 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 550 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 500 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 450 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL- 23 and TNF-alpha is about 300 mg to about 400 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 300 mg to about 350 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 100 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 300 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 400 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 500 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 600 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 700 mg. In some embodiments, the therapeutically effective amount WSGR Docket No.60790-714.601 of an inhibitor of IL-23 and TNF-alpha is at least about 800 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 900 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 1,000 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 1,100 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 1,200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 1,300 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 1,500 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 2,000 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at least about 2,500 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 2,500 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 2,000 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 1,500 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 1,300 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 1,200 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 1,100 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 1,000 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 900 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 800 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 700 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 600 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 500 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 400 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is at most about 300 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is an increment of about 135 mg, about 270 mg, about 405 mg, about 540 mg, about 675 mg, about 810 mg, about 945 mg, about 1,080 mg, about 1, 215 mg, about 1,350 mg, WSGR Docket No.60790-714.601 about 1,485 mg, about 1,620 mg, about 1,755 mg, about 1,890 mg, about 2,025 mg, about 2,160 mg, about 2,295 mg, about 2,430 mg, about 2,565 mg, about 2,700 mg, about 2,835 mg, about 2,970 mg, about 3,105 mg, 3,240 mg, 3,375 mg, 3,510 mg, 3,645 mg, 3,780 mg, 3,915 mg, 4,050 mg, 4,185 mg, 4,320 mg, about 4,455 mg, about 4,725 mg, about 4,860 mg, about 4,995 mg, about 5,130 mg, about 5,265 mg, about 5,400 mg, about 5,535
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is an increment of about 225 about 450 mg, about 675 mg, about 900 mg, about 1125 mg, about 1350 mg, about 1575 mg, about 1800 mg, about 2025 mg, about 2250 mg, about 2475 mg, about 2700 mg, about 2925 mg, about 3150 mg, about 3375 mg, about 3600 mg, about 3825 mg, about 4050 mg, about 4275 mg, about 4500 mg, about 4725 mg, about 4950 mg, about 5175 mg, about 5400 mg, about 5625 mg, about 5850 mg, about 6075 mg, about 6300 mg, about 6525 mg, about 6750 mg, about 6975 mg, about 7200 mg, about 7425 mg, about 7650 mg, about 7875 mg, about 8100 mg, about 8325 mg, about 8550 mg, about 8775 mg, about 9000 mg, about 9225 mg, about 9450 mg, about 9675 mg, about 9900 mg,
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is an increment of about 300 mg, about 600 mg, about 900 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, about 2400 mg, about 2700 mg, about 3000 mg, about 3300 mg, about 3600 mg, about 3900 mg, about 4200 mg, about 4500 mg, about 4800 mg, about 5100 mg, about 5400 mg, about 5700 mg, about 6000 mg, about 6300 mg, about 6600 mg, about 6900 mg, about 7200 mg, about 7500 mg, about 7800 mg, about 8100 mg, about 8400 mg, about 8700 mg, about 9000 mg, about 9300 mg, about 9600 mg, about 9900 mg, about 10200 mg, about 10500 mg, about 10800 mg, about 11100 mg, about 11400 mg, about 11700 mg, or about 12000 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 100 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 105 mg. In some embodiments, the therapeutically WSGR Docket No.60790-714.601 effective amount of an inhibitor of IL-23 and TNF-alpha is about 110 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 115 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL- 23 and TNF-alpha is about 120 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 125 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 130 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 135 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 140 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 145 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 150 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 155 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 160 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 165 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 170 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 175 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 180 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 185 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 190 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 195 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 200 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 205 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 210 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 215 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 220 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 225 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 230 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 235 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 240 mg.
  • the therapeutically effective WSGR Docket No.60790-714.601 amount of an inhibitor of IL-23 and TNF-alpha is about 245 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 250 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 255 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 260 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 265 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 270 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 275 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 280 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 285 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 290 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 295 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 330 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 335 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 340 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 345 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 350 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 355 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 360 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 365 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 370 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 375 mg. In some embodiments, the therapeutically effective amount of an inhibitor of WSGR Docket No.60790-714.601 IL-23 and TNF-alpha is about 380 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 385 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 390 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 395 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 400 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 405 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 410 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 415 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 420 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 425 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 430 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 435 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 440 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 445 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 450 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 455 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 460 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 465 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 470 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 475 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 480 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 485 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 490 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 495 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 500 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 505 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 510 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha WSGR Docket No.60790-714.601 is about 515 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 520 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 525 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 530 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 535 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 540 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 545 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 550 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 555 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 560 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 565 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 570 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 575 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 580 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 585 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 590 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 595 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 600 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 605 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 610 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 615 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 620 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 625 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 630 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 635 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 640 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 645 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 650 mg. In WSGR Docket No.60790-714.601 some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 655 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 660 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 665 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 670 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 675 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 680 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 685 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 690 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 695 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 700 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 705 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 710 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 715 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 720 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 725 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 730 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 735 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 740 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 745 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 750 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 755 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 760 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 765 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 770 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 775 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 780 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 785 mg.
  • the WSGR Docket No.60790-714.601 therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 790 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 795 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 800 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 805 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 810 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 815 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 820 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 825 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 830 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 835 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 840 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 845 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 850 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 855 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 860 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 865 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 870 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 875 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 880 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 885 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 890 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 895 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 900 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 905 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 910 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 915 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 920 mg. In some embodiments, the therapeutically effective WSGR Docket No.60790-714.601 amount of an inhibitor of IL-23 and TNF-alpha is about 925 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 930 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 935 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 940 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 945 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 950 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 955 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 990 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 995 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1000 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1005 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1010 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1015 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1020 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1025 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1030 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1035 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1040 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1045 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1050 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1055 mg. In some embodiments, the therapeutically effective amount of an inhibitor of WSGR Docket No.60790-714.601 IL-23 and TNF-alpha is about 1060 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1065 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1070 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1075 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1080 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1085 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1090 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1095 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1100 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1105 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1110 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1115 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1120 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1125 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1130 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1135 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1140 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1145 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1150 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1155 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1160 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1165 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1170 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1175 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1180 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1185 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1190 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1220 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1225 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1230 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1235 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1240 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1245 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1250 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1255 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1260 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1265 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1270 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1275 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1280 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1285 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1290 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1295 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1300 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1305 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1310 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1315 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1320 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1325 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1330 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1335 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1340 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1345 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1350 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1355 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1360 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1365 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1370 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1375 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1380 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1385 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1390 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1395 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1400 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1405 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1410 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1415 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1420 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1425 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1430 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1435 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1440 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1445 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1450 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1455 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1460 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1465 mg. In some embodiments, the WSGR Docket No.60790-714.601 therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1470 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1475 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1480 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1485 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1490 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1495 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1500 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1505 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1510 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1515 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1520 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1525 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1530 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1535 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1540 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1545 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1550 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1555 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1560 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1565 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1570 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1575 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1580 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1585 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1590 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1595 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1600 mg. In some embodiments, the therapeutically effective WSGR Docket No.60790-714.601 amount of an inhibitor of IL-23 and TNF-alpha is about 1605 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1610 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1615 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1620 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1625 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1630 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1635 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1640 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1645 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1650 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1655 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1660 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1665 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1670 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1675 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1680 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1685 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1690 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1695 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1700 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1705 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1710 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1715 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1720 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1725 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1730 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1735 mg.
  • the therapeutically effective amount of an inhibitor of WSGR Docket No.60790-714.601 IL-23 and TNF-alpha is about 1740 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1745 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1750 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1755 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1760 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1765 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1770 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1775 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1780 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1785 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1790 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1795 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1800 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1805 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1810 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1815 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1820 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1825 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1830 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1835 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1840 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1845 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1850 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1855 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1860 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1865 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1870 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha WSGR Docket No.60790-714.601 is about 1875 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1880 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1885 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1890 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1895 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1900 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1905 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1910 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1915 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1920 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1925 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1930 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1935 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1940 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1945 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1950 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1955 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1960 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1965 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1970 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1975 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1980 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1985 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1990 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 1995 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2000 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2005 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2010 mg. In WSGR Docket No.60790-714.601 some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2015 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2020 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2025 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2030 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2035 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2040 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2045 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2050 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2055 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2060 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2065 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2070 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2075 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2080 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2085 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2090 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2095 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2100 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2105 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2110 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2115 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2120 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2125 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2130 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2135 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2140 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2145 mg.
  • the WSGR Docket No.60790-714.601 therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2150 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2155 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2160 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2165 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2170 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2175 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2180 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2185 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2190 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2195 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2200 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2205 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2210 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2215 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2220 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2225 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2230 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2235 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2240 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2245 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2250 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2255 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2260 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2290 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2295 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2300 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2305 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2310 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2315 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2320 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2325 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2330 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2335 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2340 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2345 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2350 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2355 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2360 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2365 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2370 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2375 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2380 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2385 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2390 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2395 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2400 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2405 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2410 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2415 mg. In some embodiments, the therapeutically effective amount of an inhibitor of WSGR Docket No.60790-714.601 IL-23 and TNF-alpha is about 2420 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2425 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2430 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2435 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2440 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2445 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2450 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2455 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2460 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2465 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2470 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2475 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2480 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2485 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2490 mg.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2495 mg. In some embodiments, the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha is about 2500 mg.
  • Treatment schedule [0097] In some embodiments, inhibitors of IL-23 and TNF-alpha described herein can be administered as a single dose. In some embodiments, inhibitors of IL-23 and TNF-alpha described herein can be administered once a day. In some embodiments, inhibitors of IL-23 and TNF-alpha described herein can be administered until a therapeutic effect is achieved. In some embodiments, inhibitors of IL-23 and TNF-alpha described herein can be administered twice a day.
  • inhibitors of IL-23 and TNF-alpha described herein can be administered twice a day until a therapeutic effect is achieved.
  • Clinical outcomes [0098]
  • the treatments prescribed herein can result in improvement in outcomes for patients WSGR Docket No.60790-714.601 afflicted with autoimmune and/or inflammatory conditions.
  • the treatments prescribed herein can improve symptoms of patients afflicted with autoimmune and/or inflammatory conditions.
  • the treatments prescribed herein can provide short-term relief of patients afflicted with autoimmune and/or inflammatory conditions.
  • the treatments prescribed herein can provide long-term relief of patients afflicted with autoimmune and/or inflammatory conditions.
  • Evaluation of adverse events following therapeutic administration can be important in determining an optimal therapeutic dosage.
  • administration of placebo controls can be also be helpful in determining an optimal therapeutic dosage.
  • treatment emergent adverse events can be monitored after single administration of inhibitors of IL-23 and TNF-alpha.
  • treatment emergent adverse events can be monitored after single administration of placebo controls.
  • the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha achieves a serum concentration for the inhibitor of IL-23 and TNF-alpha, the first antigen binding domain that binds to TNF-alpha, and of the second antigen binding domain that binds to IL-23 that is below the lower limit of quantitation or minimal level of detection.
  • the wherein the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at most about 2.5 ng/mL of the inhibitor of IL-23 and TNF-alpha, at most about 80 ng/mL of the first antigen binding domain that binds to TNF-alpha, and at most about 80 ng/mL of the second antigen binding domain that binds to IL-23 in the serum of the individual.
  • the therapeutically effective amount of the inhibitor of IL-23 and TNF-alpha achieves at least about 400 nanogram per milliliter (ng/mL) of the first antigen binding domain that binds to TNF-alpha and at least about 400 nanogram per milliliter (ng/mL) of the second antigen binding domain that binds to IL-23 in the feces of the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 50,000 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 15,000 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual at about 24 to 48 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 60,000 ng/mL of the first antigen binding domain that binds to TNF- alpha and at least about 17,500 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual at about 24 to 48 hours after administering the therapeutically WSGR Docket No.60790-714.601 effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 70,000 ng/mL of the first antigen binding domain that binds to TNF- alpha and at least about 18,000 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual at about 24 to 48 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 75,000 ng/mL of the first antigen binding domain that binds to TNF- alpha and at least about 20,000 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual at about 24 to 48 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 1,500 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 1,500 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 48 to 72 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 1,700 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 1,600 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 48 to 72 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 1,850 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 1,700 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 48 to 72 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 2,000 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 1,800 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 48 to 72 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 34,000 ng/mL of the first antigen binding domain that WSGR Docket No.60790-714.601 binds to TNF-alpha and at least about 26,000 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 24 to 48 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 36,000 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 28,000 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 24 to 48 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 38,000 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 30,000 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 24 to 48 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 40,000 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 32,000 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 24 to 48 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 1,400 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 3,000 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 48 to 72 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 1,500 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 3,200 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 48 to 72 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 1,600 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 3,400 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 48 to 72 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the WSGR Docket No.60790-714.601 individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 1,700 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 3,600 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 48 to 72 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha achieves at least about 1,800 ng/mL of the first antigen binding domain that binds to TNF-alpha and at least about 3,800 ng/mL of the second antigen binding domain that binds to IL-23 in the feces of the individual in need thereof at about 48 to 72 hours after administering the therapeutically effective amount of an inhibitor of IL-23 and TNF-alpha to the individual.
  • a total cumulative fraction of a therapeutic eliminated in the feces of an individual can be calculated according to Example 4.
  • a total cumulative fraction of the inhibitor of IL-23 and TNF-alpha eliminated in the feces of the individual is at most about 0.0002%
  • a total cumulative fraction of the first antigen binding domain that binds to TNF-alpha (FeTot,TNF%) is at least about 2.00%
  • a total cumulative fraction of the second antigen binding domain that binds to IL-23 eliminated in the feces of the individual (FeTot,IL%) is at least about 1.00%.
  • the total cumulative fraction of the inhibitor of IL- 23 and TNF-alpha eliminated in the feces of the individual is at most about 0.00015%, wherein the total cumulative fraction of the first antigen binding domain that binds to TNF-alpha (Fe Tot,TNF %) is at least about 2.20%, and wherein the total cumulative fraction of the second antigen binding domain that binds to IL-23 eliminated in the feces of the individual (FeTot,IL%) is at least about 1.20%.
  • the total cumulative fraction of the inhibitor of IL-23 and TNF-alpha eliminated in the feces of the individual is at most about 0.00013%, wherein the total cumulative fraction of the first antigen binding domain that binds to TNF-alpha (FeTot,TNF%) is at least about 2.40%, and wherein the total cumulative fraction of the second antigen binding domain that binds to IL-23 eliminated in the feces of the individual (Fe Tot,IL %) is at least about 1.30%.
  • the total cumulative fraction of the inhibitor of IL-23 and TNF-alpha eliminated in the feces of the individual is at most about 0.00011%, wherein the total cumulative fraction of the first antigen binding domain that binds to TNF-alpha (Fe Tot,TNF %) is at least about 2.60%, and wherein the total cumulative fraction of the second antigen binding domain that binds to IL-23 eliminated in the feces of the individual (FeTot,IL%) is at least about 1.40%.
  • Fe Tot,TNF % is at least about 6,000 times greater than Fe Tot,IL-TNF %, and wherein WSGR Docket No.60790-714.601 Fe Tot,IL % is at least about 3,000 times greater than Fe Tot,IL-TNF %. In some embodiments, Fe Tot,TNF % is at least about 7,000 times greater than Fe Tot,IL-TNF %, and wherein Fe Tot,IL % is at least about 3,500 times greater than FeTot,IL-TNF%. In some embodiments, FeTot,TNF% is at least about 8,000 times greater than FeTot,IL-TNF%, and wherein FeTot,IL% is at least about 4,000 times greater than Fe Tot,IL-TNF %.
  • Fe Tot,TNF % is at least about 9,000 times greater than FeTot,IL-TNF%, and wherein FeTot,IL% is at least about 4,500 times greater than FeTot,IL-TNF%. In some embodiments, FeTot,TNF% is at least about 10,000 times greater than FeTot,IL-TNF%, and wherein Fe Tot,IL % is at least about 5,000 times greater than Fe Tot,IL-TNF %. [00107] A total cumulative fraction eliminated in the feces of an individual can be calculated according to Example 4.
  • a total cumulative fraction of the inhibitor of IL- 23 and TNF-alpha eliminated in the feces of the individual is at most about 0.0002%, wherein a total cumulative fraction of the first antigen binding domain that binds to TNF-alpha (FeTot,TNF%) is at least about 2.00%, and wherein a total cumulative fraction of the second antigen binding domain that binds to IL-23 eliminated in the feces of the individual (Fe Tot,IL %) is at least about 0.40%.
  • the total cumulative fraction of the inhibitor of IL-23 and TNF-alpha eliminated in the feces of the individual is at most about 0.00019%
  • the total cumulative fraction of the first antigen binding domain that binds to TNF-alpha (Fe Tot,TNF %) is at least about 2.10%
  • the total cumulative fraction of the second antigen binding domain that binds to IL-23 eliminated in the feces of the individual (FeTot,IL%) is at least about 0.38%.
  • the total cumulative fraction of the inhibitor of IL-23 and TNF-alpha eliminated in the feces of the individual is at most about 0.00018%
  • the total cumulative fraction of the first antigen binding domain that binds to TNF-alpha (FeTot,TNF%) is at least about 2.20%
  • the total cumulative fraction of the second antigen binding domain that binds to IL-23 eliminated in the feces of the individual is at least about 0.36%.
  • Fe Tot,TNF % is at least about 6,000 times greater than FeTot,IL-TNF%, and wherein FeTot,IL% is at least about 1,500 times greater than Fe Tot,IL-TNF %. In some embodiments, Fe Tot,TNF % is at least about 7,000 times greater than Fe Tot,IL- TNF %, and wherein Fe Tot,IL % is at least about 1,600 times greater than Fe Tot,IL-TNF %. In some embodiments, FeTot,TNF% is at least about 8,000 times greater than FeTot,IL-TNF%, and wherein FeTot,IL% is at least about 1,700 times greater than FeTot,IL-TNF%.
  • Fe Tot,TNF % is at least about 9,000 times greater than Fe Tot,IL-TNF %, and wherein Fe Tot,IL % is at least about 1,800 times greater than FeTot,IL-TNF%. In some embodiments, FeTot,TNF% is at least about 10,000 times greater than FeTot,IL-TNF%, and wherein FeTot,IL% is at least about 2,000 times greater than Fe Tot,IL-TNF %.
  • WSGR Docket No.60790-714.601 Non-limiting examples of patient selection criteria
  • an individual being treated with inhibitors of IL-23 and TNF-alpha described herein may be at least 18 years of age. In some embodiments, an individual being treated with inhibitors of IL-23 and TNF-alpha described herein may be at most 55, 60, 65, 70, or 75 years of age. In some embodiments, an individual being treated with inhibitors of IL-23 and TNF-alpha described herein may be male. In some embodiments, an individual being treated with inhibitors of IL-23 and TNF-alpha described herein may be female. In some embodiments, an individual being treated with inhibitors of IL-23 and TNF-alpha described herein may not be gender based.
  • an individual being treated with inhibitors of IL-23 and TNF-alpha described herein can be a healthy volunteer. In some embodiments, an individual being treated with inhibitors of IL-23 and TNF-alpha described herein can be of any ethnic origin. In some embodiments, an individual being treated with inhibitors of IL-23 and TNF-alpha described herein may have a body mass index (BMI) of about 18.0 to 35.0 kg/m 2 (inclusive). In some embodiments, an individual being treated with inhibitors of IL-23 and TNF-alpha described herein can be healthy as determined by a responsible physician.
  • BMI body mass index
  • an individual being treated with inhibitors of IL-23 and TNF- alpha described herein can have normal bowel habits as defined by usual passage of daily stool. [00109] In some embodiments, an individual being treated with inhibitors of IL-23 and TNF- alpha described herein may not have a clinically relevant history of abnormal physical or mental health. In some embodiments, an individual being treated with inhibitors of IL-23 and TNF- alpha described herein may not have clinically relevant abnormal laboratory results. In some embodiments, an individual being treated with inhibitors of IL-23 and TNF-alpha described herein may not have history or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug.
  • an individual being treated with inhibitors of IL-23 and TNF-alpha described herein may not have any other concomitant disease or condition that could interfere with the conduct of the study.
  • an individual being treated with inhibitors of IL-23 and TNF-alpha described herein may not have veins unsuitable for venepuncture and/or cannulation.
  • WSGR Docket No.60790-714.601 EXAMPLES [00110] The following illustrative examples are representative of embodiments of compositions and methods described herein and are not meant to be limiting in any way. Table 1: Amino acid sequences or polynucleotide sequences disclosed are represented herein.
  • TNF-alpha/IL-23 dual inhibitor can inhibit TNF-alpha and IL-23 activity while intact and after trypsin cleavage, and its liberated monomer arms are functional and resistant to human fecal proteases.
  • TNF-alpha/IL-23 dual inhibitor a bispecific anti-TNF–alpha/anti-IL–23 domain antibody (SEQ ID NO: 201; hereinafter in the examples, “TNF-alpha/IL-23 dual inhibitor”) and its monomeric arms were evaluated after exposure to trypsin.
  • TNF-alpha/IL-23 dual inhibitor WSGR Docket No.60790-714.601 contains two humanized single domain antibodies targeting TNF-alpha (SEQ ID NO: 118) and IL-23p19 (SEQ ID NO: 13) connected by a trypsin-labile linker (SEQ ID NO: 302), which can enable monomer separation within the small intestine.
  • the anti-TNF–alpha single domain antibody is hereinafter referred to in the examples as “TNF-alpha inhibitor” and the anti-IL–23 single domain antibody is hereinafter referred to in the examples as “IL-23 inhibitor”.
  • the central lysine linker of TNF-alpha/IL-23 dual inhibitor can be cleaved in intestinal supernatants ( Figure 2A), yielding cleavage products comprising a liberated anti-TNF–alpha monomer arm (SEQ ID NO: 203; hereinafter in the examples, “liberated–anti-TNF”) and a liberated anti-IL–23 monomer arm (SEQ ID NO: 204; hereinafter in the examples, “liberated–anti-IL-23”).
  • TNF-alpha inhibitor TNF-alpha/IL-23 dual inhibitor, and IL-23 inhibitor were produced and purified from yeast.
  • TNF-alpha/IL-23 dual inhibitor was incubated in pooled human fecal supernatant (HFS), and TNF-alpha/IL-23 dual inhibitor-liberated monomer arms were purified from the digestive mixture.
  • HFS human fecal supernatant
  • TNF-alpha inhibitor TNF- alpha/IL-23 dual inhibitor
  • IL-23 inhibitor trypsin-liberated TNF-alpha/IL-23 dual inhibitor monomer arms
  • ELISAs whereby inhibitor molecules competed with biotinylated adalimumab (anti-TNF–alpha IgG1) or interrupted IL-23/IL-23-receptor binding.
  • the competitive ELISA data indicate that TNF-alpha/IL-23 dual inhibitor and liberated monomer arms retain full anti-TNF–alpha and anti-IL–23 activity after exposure to trypsin (Figure 2B-2C).
  • the competitive ELISA data also show that the liberated anti-IL–23 monomer arm, liberated–anti-IL-23, can be more potent than the anti-IL–23 single domain antibody (IL-23 inhibitor) parent ( Figure 2C and Table 2).
  • Table 2 IC 50 values of TNF-alpha/IL-23 dual inhibitor, liberated–anti-IL-23, and liberated– anti-TNF.
  • the stability of TNF-alpha/IL-23 dual inhibitor and its monomer arms post-cleavage were also evaluated. TNF-alpha/IL-23 dual inhibitor and the parent monomers, TNF-alpha inhibitor and IL-23 inhibitor, were incubated in pooled human fecal supernatant (HFS) for 4 hours.
  • HFS human fecal supernatant
  • Time 0 hour and 4 hour samples were compared for anti-TNF–alpha activity in the biotinylated adalimumab assay (TNF-alpha inhibitor and TNF-alpha/IL-23 dual inhibitor) or anti-IL-23 WSGR Docket No.60790-714.601 activity in the IL-23/IL-23R ELISA (IL-23 inhibitor and TNF-alpha/IL-23 dual inhibitor). The remaining activity in each sample at 4 hours was calculated as a survival percentage against the 0 hour time point ( Figure 2D).
  • the assay results show that the TNF-alpha/IL-23 dual inhibitor and its cleavage products are resistant to human fecal proteases as evidenced by retention of functional activity after exposure to HFS.
  • UC ulcerative colitis
  • Biopsies were collected from four different UC patients and incubated for 24 hours with single domain antibody treatments (Control (ID2A) 225 nM; TNF-alpha inhibitor 75 nM; IL-23 inhibitor 150 nM; or TNF-alpha inhibitor 75 nM + IL-23 inhibitor 150 nM combined) and analyzed for the extent of phosphorylation of tyrosine kinase receptors and signalling proteins that can be increased in inflamed intestinal tissue (Figure 2E and Figure 2F). Lysates were analyzed on R&D proteome profiler human phosphokinase arrays and phosphointensity data were averaged for each treatment. Heatmap shadings were applied relative to the averaged signal of each phosphoprotein in the final array data set.
  • Example 2 Cynomolgus monkey in vivo pharmacokinetics study of a bispecific anti-TNF– alpha/anti-IL–23 domain antibody for the treatment of inflammatory bowel disease
  • the labile peptide linker in TNF-alpha/IL-23 dual inhibitor is functional and both dual inhibitor-liberated TNF-alpha and IL-23 monomer arms are stable in the intestinal environment of non-human primates.
  • TNF-alpha/IL-23 dual inhibitor was produced and purified from yeast.10 non-human primates (NHPs), 5 male and 5 female cynomolgus monkeys, were dosed orally twice a day for 42 days (135 mg/dose, 270 mg per day total). On Day 42, fecal samples and intestinal samples were collected and analyzed for the presence of TNF-alpha/IL-23 dual inhibitor, the TNF- alpha/IL-23 dual inhibitor-liberated anti-TNF–alpha monomer arm (“liberated–anti-TNF”), and the liberated anti-IL–23 monomer arm (“liberated–anti-IL-23”).
  • the data WSGR Docket No.60790-714.601 liberated–anti-TNF range: 0.01-1.8 ⁇ M and liberated–anti-IL-23 range: 0.07-14.7 ⁇ M; Figure 3A).
  • the data also show that 9/10 animals were positive for liberated–anti-TNF at least one time point and that 10/10 animals were positive for liberated–anti-IL-23 at least one time point (Table 3).
  • Table 3 [00118] 6 animals were given a third oral dose of TNF-alpha/IL-23 dual inhibitor at the 24- hour time point and culled 4 hours after this final dose. Intestinal contents were collected from 7 intestinal sections (stomach, duodenum, jejunum, ileum, caecum, colon and rectum) at this 4- hour time point where concentrations of liberated–anti-TNF and liberated–anti-IL-23 were quantified by ELISA ( Figure 3B and Table 4).
  • Example 3 Human clinical study of orally delivered bispecific anti-TNF–alpha/anti-IL–23 domain antibody for the treatment of inflammatory bowel disease
  • Orally administered TNF-alpha/IL-23 dual inhibitor is safe and well tolerated, selective to the gut, and efficiently cleaved after oral dosing.
  • the safety, tolerability, and pharmacokinetics of TNF-alpha/IL-23 dual inhibitor when orally delivered for the treatment of IBD was evaluated in a three-part Phase 1 clinical study.
  • TNF-alpha/IL-23 dual inhibitor can inhibit TNF-alpha and IL-23 activity while intact and after trypsin cleavage.
  • SAD single ascending doses
  • MD multiple doses
  • TNF-alpha/IL-23 dual inhibitor dose 135 mg (Cohort 1), 405 mg (Cohort 2), 1215 mg (Cohort 3), or 3645 mg (Cohort 4), or placebo.
  • Safety and tolerability, fecal and serum concentrations of TNF-alpha/IL-23 dual inhibitor and its monomers were assessed at predetermined times via antigen-binding ELISA assays.7 adverse events (AE) of mild or moderate severity observed in Part 1.
  • AE adverse events
  • One AE of mild intensity may be treatment-related was observed in the lowest dose cohort.
  • TNF-alpha/IL-23 dual inhibitor and its monomers were not detected in serum.
  • Table 6 Summary fecal concentrations of liberated–anti-TNF following a single dose of TNF- alpha/IL-23 dual inhibitor (405 mg).
  • Table 7 Summary fecal concentrations of liberated–anti-TNF following a single dose of TNF- alpha/IL-23 dual inhibitor (1215 mg).
  • Table 8 Summary fecal concentrations of liberated–anti-TNF following a single dose of TNF- alpha/IL-23 dual inhibitor (3645 mg).
  • Table 9 Summary fecal concentrations of liberated–anti-IL-23 following a single dose of TNF- alpha/IL-23 dual inhibitor (135 mg).
  • Table 10 Summary fecal concentrations of liberated–anti-IL-23 following a single dose of TNF-alpha/IL-23 dual inhibitor (405 mg).
  • Table 11 Summary fecal concentrations of liberated–anti-IL-23 following a single dose of TNF-alpha/IL-23 dual inhibitor (1215 mg).
  • Table 12 Summary fecal concentrations of liberated–anti-IL-23 following a single dose of TNF-alpha/IL-23 dual inhibitor (3645 mg).
  • Table 13 Summary fecal concentrations of TNF-alpha/IL-23 dual inhibitor following a single dose of TNF-alpha/IL-23 dual inhibitor (135 mg).
  • Table 14 Summary fecal concentrations of TNF-alpha/IL-23 dual inhibitor following a single dose of TNF-alpha/IL-23 dual inhibitor (405 mg).
  • Table 15 Summary fecal concentrations of TNF-alpha/IL-23 dual inhibitor following a single dose of TNF-alpha/IL-23 dual inhibitor (1215 mg).
  • Table 16 Summary fecal concentrations of TNF-alpha/IL-23 dual inhibitor following a single dose of TNF-alpha/IL-23 dual inhibitor (3645 mg).
  • Table 16 Summary fecal concentrations of TNF-alpha/IL-23 dual inhibitor following a single dose of TNF-alpha/IL-23 dual inhibitor (3645 mg).
  • Part 2 of the clinical study evaluated the safety and tolerability of MD of TNF- alpha/IL-23 dual inhibitor, the concentration of intact TNF-alpha/IL-23 dual inhibitor and its monomers (liberated–anti-TNF and liberated–anti-IL-23) in serum, feces, and urine, and the incidence of anti-drug antibodies. Healthy subjects were randomized 8:2 to active (approximately 1200 mg PO, twice daily) and placebo (PO, twice daily) treatment administered for 7 days.
  • TNF-alpha/IL-23 dual inhibitor and its monomers were assessed at predetermined times. No AEs were observed in Part 2. TNF-alpha/IL-23 dual inhibitor and its monomers were not detected in serum. Fecal concentrations of active TNF-alpha/IL-23 dual inhibitor monomers were observed during all dosing days (Tables 17-18). The highest fecal concentrations observed were Tables 17-18). Monomer fecal concentrations were observed across all dosing days, peaking at >1700 ⁇ g/mL (Tables 17-18).
  • Table 17 Summary fecal concentrations of liberated–anti-TNF following a twice daily dose of 1215 mg TNF-alpha/IL-23 dual inhibitor (total 2430 mg).
  • Table 18 Summary fecal concentrations of liberated–anti-IL-23 following a twice daily dose of 1215 mg TNF-alpha/IL-23 dual inhibitor (total 2430 mg).
  • Table 19 Summary fecal concentrations of TNF-alpha/IL-23 dual inhibitor following a twice daily dose of 1215 mg TNF-alpha/IL-23 dual inhibitor (total 2430 mg).
  • TNF-alpha/IL-23 dual inhibitor fecal concentrations were on WSGR Docket No.60790-714.601 Tables 5-19). TNF-alpha/IL-23 dual inhibitor was well tolerated at all tested doses. Systemic exposure of TNF-alpha/IL-23 dual inhibitor and its monomers was not observed, supporting its gut selectivity. Low levels of intact TNF-alpha/IL-23 dual inhibitor and high levels of TNF- alpha/IL-23 dual inhibitor monomers in feces confirmed that TNF-alpha/IL-23 dual inhibitor is efficiently cleaved after oral dosing.
  • TNF-alpha/IL-23 dual inhibitor can be an orally administered for the treatment of IBD.
  • TNF-alpha/IL-23 dual inhibitor can be cleaved by HFS and NHP gut matrices into its monomer arms.
  • Liberated–anti-TNF and liberated–anti-IL- 23 monomer arms can be stable and retain target binding efficacy after exposure to trypsin, HFS, and NHP gut matrices.
  • TNF-alpha inhibitor and IL-23 inhibitor in combination can decrease protein phosphorylation in UC patient biopsies, which can confirm the benefit of dual targeting.
  • TNF-alpha/IL-23 dual inhibitor and its monomer arms can exhibit rapid serum clearance, which may suggest low risk of systemic immunosuppression in IBD patients.
  • Example 4 Human clinical study of orally delivered bispecific anti-TNF–alpha/anti-IL–23 domain antibody for the treatment of inflammatory bowel disease [00126] Orally administered TNF-alpha/IL-23 dual inhibitor is selective to the GI tract with minimal systemic exposure. This administered TNF-alpha/IL-23 dual inhibitor is efficiently cleaved, exhibiting comparatively low levels of intact TNF-alpha/IL-23 dual inhibitor and high levels of TNF-alpha and IL-23 monomer after oral dosing.
  • TNF-alpha/IL-23 dual inhibitor Cleavage of the TNF-alpha/IL-23 dual inhibitor by intestinal proteases yields an anti-TNF-alpha monomer arm (“liberated–anti-TNF”) and an anti-IL-23 monomer arm (“liberated–anti-IL-23”).
  • the molecular weight of the dual TNF- alpha/IL-23 dual inhibitor is about 27.2 kilodaltons (kDa).
  • the molecular weight of the monomeric anti-TNF-alpha and anti-IL-23 arms are about 13.4 kDa and 13.9 kDa, respectively.
  • TNF-alpha/IL-23 dual inhibitor dose 135 mg (Cohort 1), 405 mg (Cohort 2), 1215 mg (Cohort 3), or 3645 mg (Cohort 4), or placebo.
  • Safety and tolerability, fecal and serum concentrations of TNF-alpha/IL-23 dual inhibitor and its monomers were assessed at predetermined times via antigen-binding ELISA assays.
  • the serum concentration of TNF-alpha/IL-23 dual inhibitor across all doses administered were below the lower limit of quantitation of 2.5 nanogram per microliter (ng/mL; data not shown).
  • Fecal concentrations of TNF-alpha/IL-23 dual inhibitor were about 1,000 times lower than fecal concentrations of TNF-alpha/IL-23 dual inhibitor monomers ( Figure 5A-5B and Tables 20-23).
  • Fecal concentrations of active TNF-alpha/IL-23 dual inhibitor monomers were detected at all dose levels, peaking between about 20 and 60 hours after administration, with generally higher concentrations observed in higher-dose cohorts ( Figure 5A-5B and Tables 24- 31).
  • Liberated–anti-IL-23 was detected in stool in all dose cohorts, concentrations generally increased with each single ascending dose, similar concentrations observed in Cohort 3 (1215 mg) and Cohort 4 (3645 mg) ( Figure 5A-5B and Tables 24-27).
  • Table 20 Individual and Summary Fecal Concentrations of TNF-ALPHA/IL-23 DUAL INHIBITOR Following Single Oral Dosing of 135mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • Table 21 Individual and Summary Fecal Concentrations of TNF-ALPHA/IL-23 DUAL INHIBITOR Following Single Oral Dosing of 405mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • Table 22 Individual and Summary Fecal Concentrations of TNF-ALPHA/IL-23 DUAL INHIBITOR Following Single Oral Dosing of 1215mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • Table 23 Individual and Summary Fecal Concentrations of TNF-ALPHA/IL-23 DUAL INHIBITOR Following Single Oral Dosing of 3645mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • Table 24 Individual and Summary Fecal Concentrations of LIBERATED–IL-23 Following Single Oral Dosing of 135mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • WSGR Docket No.60790-714.601 Table 25: Individual and Summary Fecal Concentrations of LIBERATED–IL-23 Following Single Oral Dosing of 405mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • WSGR Docket No.60790-714.601 Table 26: Individual and Summary Fecal Concentrations of LIBERATED–IL-23Following Single Oral Dosing of 1215mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • Table 27 Individual and Summary Fecal Concentrations of LIBERATED–IL-23Following Single Oral Dosing of 3645mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • NS- No Sample NC- NotCalculated LLOQ - Lower Limit of Quantification 80 ng/ml WSGR Docket No.60790-714.601
  • Table 28 Individual and Summary Fecal Concentrations of Liberated–anti-TNF Following Single Oral Dosing of 135mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • Table 29 Individual and Summary Fecal Concentrations of Liberated–anti-TNF Following Single Oral Dosing of 405mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • Table 30 Individual and Summary Fecal Concentrations of Liberated–anti-TNF Following Single Oral Dosing of 1215mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • Table 31 Individual and Summary Fecal Concentrations of Liberated–anti-TNF Following Single Oral Dosing of 3645mg TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 1.
  • Fecal pharmacokinetic results can be quantified by at least the parameters and calculations shown in Table 32.
  • a total cumulative fraction of the inhibitor of IL-23 and TNF-alpha eliminated in the feces of the individual (Fe Tot,IL-TNF %) was about 0.000103%
  • a total cumulative fraction of the first antigen binding domain that binds to TNF-alpha (FeTot,TNF%) was about 2.70%
  • a total cumulative fraction of the second antigen binding domain that binds to IL-23 eliminated in the feces of the individual was about 1.47%.
  • FeTot,TNF% was at least about 26,213 times greater than FeTot,IL-TNF% and FeTot,IL% was at least about 14,271 times greater than FeTot,IL-TNF%.
  • a total cumulative fraction of the inhibitor of IL-23 and TNF-alpha eliminated in the feces of the individual was about 0.000177%
  • a total cumulative fraction of the first antigen binding domain that binds to TNF-alpha (FeTot,TNF%) was about 2.33%
  • a total cumulative fraction of the second antigen binding domain that binds to IL-23 eliminated in the feces of the individual was about 0.43%.
  • Fe Tot,TNF % was at least about 13,163 times greater than FeTot,IL-TNF% and FeTot,IL% was at least about 2,429 times greater than FeTot,IL-TNF%.
  • the fecal pharmacokinetic results can be derived from Tables 33-38.
  • Table 35 Individual and Summary Total Fecal Ae and Fe for liberated–anti-TNF following Single Oral Dosing of 1215mg TNF-alpha/IL-23 dual inhibitor in Part 1.
  • Table 36 Individual and Summary Total Fecal Ae and Fe for TNF-alpha/IL-23 dual inhibitor following Single Oral Dosing of 3645mg TNF-alpha/IL-23 dual inhibitor in Part 1.
  • WSGR Docket No.60790-714.601 Table 37 Individual and Summary Total Fecal Ae and Fe for liberated–anti-IL-23 following Single Oral Dosing of 3645mg TNF-alpha/IL-23 dual inhibitor in Part 1.
  • Table 38 Individual and Summary Total Fecal Ae and Fe for liberated–anti-TNF following Single Oral Dosing of 3645mg TNF-alpha/IL-23 dual inhibitor in Part 1.
  • WSGR Docket No.60790-714.601 Part 2 of the clinical study evaluated the safety and tolerability of MD of TNF- alpha/IL-23 dual inhibitor, the concentration of intact TNF-alpha/IL-23 dual inhibitor and its monomers (liberated–anti-TNF and liberated–anti-IL-23) in serum, feces, and urine, and the incidence of anti-drug antibodies. Healthy subjects were randomized 8:2 to active (approximately 1200 mg PO, twice daily) and placebo (PO, twice daily) treatment administered for 7 days.
  • TNF-alpha/IL-23 dual inhibitor Safety and tolerability, fecal, serum and urine concentrations of TNF-alpha/IL-23 dual inhibitor and its monomers, and ADA levels were assessed at predetermined times.
  • the serum concentration of TNF-alpha/IL-23 dual inhibitor were below the lower limit of quantitation of 2.5 nanogram per microliter (ng/mL; data not shown).
  • the serum concentration of liberated–anti-TNF and liberated–anti-IL-23 were also below the lower limit of quantitation of 80 ng/mL (data not shown). Thus, there was no evidence of systemic absorption of the TNF-alpha/IL-23 dual inhibitor and its corresponding monomer arms.
  • WSGR Docket No.60790-714.601 Table 40: Individual and Summary Fecal Concentrations of Liberated–anti-IL-23 Following Twice Daily Oral Dosing of 1215 mg of TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 2.
  • WSGR Docket No.60790-714.601 Table 41: Individual and Summary Fecal Concentrations of Liberated–anti-TNF Following Twice Daily Oral Dosing of 1215 mg of TNF-ALPHA/IL-23 DUAL INHIBITOR in Part 2.
  • WSGR Docket No.60790-714.601 [00136] The data from Example 4 indicate that there was no evidence of systemic absorption of the TNF-alpha/IL-23 dual inhibitor.
  • TNF-alpha/IL-23 dual inhibitor After single and multiple oral dose administration of TNF-alpha/IL-23 dual inhibitor, the amount of TNF-alpha/IL-23 dual inhibitor excreted as a fraction of the administered dose was negligible. For liberated–anti-TNF and liberated–anti-IL- 23 this fraction was several-fold higher. These observations suggest that most of the TNF- alpha/IL-23 dual inhibitor dose was converted to liberated–anti-TNF and liberated–anti-IL-23 after oral administration. Of note, after oral dosing of TNF-alpha/IL-23 dual inhibitor at 1215 mg twice daily, the concentrations of liberated–anti-TNF and liberated–anti-IL-23 measured in feces were several-fold higher than those observed for TNF-alpha/IL-23 dual inhibitor.
  • TNF-alpha/IL-23 dual inhibitor can be orally administered for the treatment of IBD.
  • TNF-alpha/IL-23 dual inhibitor can be cleaved by HFS and NHP gut matrices into its monomer arms.
  • Liberated–anti-TNF and liberated–anti-IL-23 monomer arms can be stable and retain target binding efficacy after exposure to trypsin, HFS, and NHP gut matrices.
  • TNF-alpha inhibitor and IL-23 inhibitor in combination can decrease protein phosphorylation in UC patient biopsies, which can confirm the benefit of dual targeting.
  • TNF-alpha/IL-23 dual inhibitor and its monomer arms can exhibit rapid serum clearance, which may suggest low risk of systemic immunosuppression in IBD patients.

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Abstract

L'invention concerne une méthode de traitement d'une affection auto-immune ou inflammatoire du tractus gastro-intestinal chez un individu en ayant besoin, la méthode comprenant l'administration d'une quantité thérapeutiquement efficace d'un inhibiteur de l'interleukine 23 (IL-23) et du facteur de nécrose tumorale alpha (TNF-alpha) à l'individu, la quantité thérapeutiquement efficace étant d'environ 100 milligrammes à environ 11000 milligrammes.
PCT/US2024/049834 2023-10-05 2024-10-03 Dosages d'inhibiteurs d'il-23 et de tnf-alpha destinés à être utilisés dans des troubles auto-immuns et inflammatoires Pending WO2025076251A1 (fr)

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J. WANG ET AL.: "OP061: A NOVEL BISPECIFIC NANOBODY TARGETING TNF-A AND IL -23 DISPLAYS POTENT ANTI-DISEASE EFFECTS IN DSS-INDUCED COLITIS MODEL", UNITED EUROPEAN GASTROENTEROL JOURNAL, SAGE, GB, vol. 10, no. 8, 8 October 2022 (2022-10-08), GB , pages 52, XP009562320, ISSN: 2050-6406 *
ROBERTS KEVIN J., CUBITT MARION F., CARLTON TIMOTHY M., RODRIGUES-DUARTE LURDES, MAGGIORE LUANA, CHAI RAY, CLARE SIMON, HARCOURT K: "Preclinical development of a bispecific TNFα/IL-23 neutralising domain antibody as a novel oral treatment for inflammatory bowel disease", SCIENTIFIC REPORTS, NATURE PUBLISHING GROUP, US, vol. 11, no. 1, US , pages 19422 - 19422-14, XP093269080, ISSN: 2045-2322, DOI: 10.1038/s41598-021-97236-0 *

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