WO2024054868A1 - Protéine de fusion fc d'il-2 destinée à être utilisée dans des méthodes pour le traitement du psoriasis en plaque et de la dermatite atopique - Google Patents

Protéine de fusion fc d'il-2 destinée à être utilisée dans des méthodes pour le traitement du psoriasis en plaque et de la dermatite atopique Download PDF

Info

Publication number
WO2024054868A1
WO2024054868A1 PCT/US2023/073577 US2023073577W WO2024054868A1 WO 2024054868 A1 WO2024054868 A1 WO 2024054868A1 US 2023073577 W US2023073577 W US 2023073577W WO 2024054868 A1 WO2024054868 A1 WO 2024054868A1
Authority
WO
WIPO (PCT)
Prior art keywords
days
fusion protein
subject
weeks
dose
Prior art date
Application number
PCT/US2023/073577
Other languages
English (en)
Inventor
Raphael Clynes
Ralph ZITNIK
Shelley BELOUSKI
Original Assignee
Xencor, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xencor, Inc. filed Critical Xencor, Inc.
Publication of WO2024054868A1 publication Critical patent/WO2024054868A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]

Definitions

  • a method of treating plaque psoriasis or atopic dermatitis in a subject in need thereof comprising subcutaneously administering to the subject an interleukin-2 (IL-2) Fc fusion protein, wherein the IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject every 12 to 16 days or every 27 to 31 days at a dose of about 0.003 mg/kg to about 0.100 mg/kg.
  • IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the IL-2 Fc fusion protein is subcutaneously administered to the subject every 12 to 16 days or every 27 to 31 days at a dose of
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least four cycles. In some aspects, the subject is administered the dose of about 0.007 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose - 1 - NAI-1537985011v1 of about 0.007 mg/kg every 14 days or every 30 days. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least four cycles.
  • the subject is administered the dose of about 0.015 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose of about 0.015 mg/kg every 14 days or every 30 days. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles. In some aspects, the subject is administered the dose of about 0.025 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose of about 0.025 mg/kg every 14 days or every 30 days.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles. In some aspects, the subject is administered the dose of about 0.040 mg/kg every 13 to 15 days or every 28 to 30 days. In some aspects, the subject is administered the dose of about 0.040 mg/kg every 14 days or every 30 days. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles. In some aspects, the subject is administered the dose of about 0.065 mg/kg every 13 to 15 days or every 28 to 30 days.
  • the subject is administered the dose of about 0.065 mg/kg every 14 days or every 30 days.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 12 to 16 days or every 27 to 31 days for about or at least about four cycles.
  • the subject is administered the dose of about 0.100 mg/kg every 13 to 15 days or every 28 to 30 days.
  • the subject is administered the dose of about 0.100 mg/kg every 14 days or every 30 days.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.007 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for at least 3 - 2 - NAI-1537985011v1 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for at least 4 cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.007 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.015 mg/kg every 14 days or every 30 days for at least two cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.015 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.025 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for at least 4 cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.025 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL- 2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.040 mg/kg every 14 days or every 30 days for at least two cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.040 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose - 3 - NAI-1537985011v1 of about 0.065 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles.
  • the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.065 mg/kg every 14 days or every 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for at least 4 cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.065 mg/kg for 4 cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 12 to 16 days or every 27 to 31 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 13 to 15 days or every 28 to 30 days for at least two cycles. In some aspects, the IL-2 Fc fusion protein is subcutaneously administered to the subject at a dose of about 0.100 mg/kg every 14 days or every 30 days for at least two cycles.
  • the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for at least 3 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for at least 4 cycles. In some aspects, the IL-2 Fc fusion protein is administered at a dose of about 0.100 mg/kg for 4 cycles. [0007] In some aspects, the IL-2 Fc fusion protein is XmAb®27564 (XmAb®564). In some aspects, the IL-2 Fc fusion protein is a biosimilar, biobetter, or bioequivalent of XmAb®27564 (XmAb®564). In some aspects, the subject is a human subject.
  • the human subject is 18 to 75 years of age. In some aspects, the human subject has a body surface area (BSA) of psoriasis of ⁇ 2%. In some aspects, the human subject has an Investigator’s Global Assessment of 2 (mild) to 4 (severe). In some aspects, the subject has not previously been administered a therapy for plaque psoriasis or atopic dermatitis. In some aspects, the subject has previously been administered a therapy for plaque psoriasis or atopic dermatitis. [0008] In some aspects, the subject has not previously been administered an oral treatment for plaque psoriasis or atopic dermatitis in the 4 weeks prior to the administration of the IL-2-Fc fusion protein.
  • BSA body surface area
  • the subject has not previously been administered a biologic treatment for plaque psoriasis or atopic dermatitis for 12 weeks or 5 half-lives, whichever is longer, prior to the administration of the IL-2-Fc fusion protein.
  • the subject has - 4 - NAI-1537985011v1 not previously been administered a phototherapy in the 4 weeks prior to the administration of the IL-2-Fc fusion protein.
  • the subject has not previously been administered a topical treatment for psoriasis or atopic dermatitis in the 2 weeks prior to the administration of the IL-2-Fc fusion protein.
  • the subject does not have any other inflammatory or dermatological condition besides the plaque psoriasis or atopic dermatitis. In some aspects, the subject does not have any other form of psoriasis or atopic dermatitis.
  • the administering of the IL-2 Fc fusion protein results in an increase in the number of CD4+ regulatory T (Treg) cells in the subject as compared to before the administering.
  • the number of CD4+ Treg cells is increased about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-fold, about 12-fold, about 13-fold, about 14-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, about 25-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, or about 100- fold.
  • the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD4+ effector T (Teff) cells in the subject as compared to before the administering.
  • the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of NK cells in the subject as compared to before the administering.
  • the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD4+ conventional T (Tcon) cells in the subject as compared to before the administering.
  • the administering of the IL-2 Fc fusion protein does not result in a significant increase in the number of CD8+ Tcon T cells in the subject as compared to before the administering.
  • the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a Psoriasis Area and Severity Index (PASI) score of about 50% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein.
  • the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a PASI score of about 75% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein.
  • the administering of the IL-2 Fc fusion protein results in the subject having an improvement of a PASI score of about 90% over the subject’s baseline PASI score prior to the administering of the IL-2 Fc fusion protein.
  • the administering of the IL-2 Fc fusion protein results in the subject having a Static Investigator’s Global Assessment (sIGA) score of 0, 1 or 2.
  • the administering of the IL-2 Fc fusion protein results in the subject having an improvement in a Dermatology Life Quality Index (DLQI) score as compared to the baseline DLQI score in the subject prior to the administering of the IL-2 Fc fusion protein.
  • DLQI Dermatology Life Quality Index
  • the administering of the IL-2 Fc fusion protein results in the subject having a decrease in body surface area (BSA) of psoriasis or atopic dermatitis as compared to the baseline BSA of psoriasis or atopic dermatitis in the subject prior to the administering of the IL-2 Fc fusion protein.
  • BSA of psoriasis is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 60%, about 80%, about 90%, or about 100%.
  • the subject does not have another type of psoriasis besides the plaque psoriasis, or the subject has atopic dermatitis.
  • a method of treating plaque psoriasis or atopic dermatitis in a subject in need thereof comprising subcutaneously administering to the subject a single dose of an interleukin-2 (IL-2) Fc fusion protein, wherein the IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the single dose is an amount of about 0.003 mg/kg to about 0.1 mg/kg.
  • IL-2 Fc fusion protein comprises: a) a first monomer comprising an amino acid sequence of SEQ ID NO: 2; and b) a second monomer comprising an amino acid sequence of SEQ ID NO: 3; wherein the single dose is an amount of about 0.003 mg/kg to about 0.1 mg/kg.
  • the single dose is an amount of 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, 0.065 mg/kg, or 0.1 mg/kg. In some aspects, the single dose is an amount of 0.065 mg/kg.
  • the IL-2 Fc fusion protein is XmAb®27564 (XmAb®564). In some aspects, the IL-2 Fc fusion protein is a biosimilar, biobetter, or bioequivalent of XmAb®27564 (XmAb®564). In some aspects, the subject is a human subject.
  • the administering of the IL-2 Fc fusion protein results in an increase in the number of CD25 bright Treg cells in the subject as compared to baseline. In some aspects, the administering of the IL-2 Fc fusion protein results in an increase in CD25 bright Treg/Tcon ratio in the subject as compared to baseline. In some aspects, the administering of the IL-2 Fc fusion protein results in an increase in the number of total Treg cells in the subject as compared to baseline. In some aspects, the total Treg cells comprises CD25 bright FoxP3+ CD4 Treg cells.
  • the increase is an increase of about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11-fold, about 12- - 6 - NAI-1537985011v1 fold, about 13-fold, about 14-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, about 25-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, or about 100-fold.
  • the increase is an increase of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or more than about 100%.
  • FIG.1 depicts an IL-2 Fc fusion protein of the disclosure.
  • FIG.1 shows the structure of an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) engineered for reduced potency plus Treg selectivity.
  • FIGS.2A-2B each depict a study design of XmAb ® 27564 with an ascending dose escalation.
  • FIGS.3A-3C depict a study design using XmAb ® 27564.
  • FIG.3A depicts a dose escalation of XmAb ® 27564 for psoriasis and FIG.3B for atopic dermatitis.
  • the first cohort is administered a dose of 0.007 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the second cohort is administered a dose of 0.015 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the third cohort is administered a dose of 0.025 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the fourth cohort is administered a dose of 0.040 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the fifth cohort is administered a dose of 0.065 mg/kg of XmAb ® 27564 every 14 days for 4 doses; and the sixth cohort is administered a dose of 0.100 mg/kg of XmAb ® 27564 every 14 days for 4 doses (FIG.3A).
  • the first cohort is administered a dose of 0.015 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the second cohort is administered a dose of 0.025 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the third cohort is administered a dose of 0.040 mg/kg of XmAb ® 27564 every 14 days for 4 doses; the fourth cohort is administered a dose of 0.065 mg/kg of XmAb ® 27564 every 14 days for 4 doses; and the fifth - 7 - NAI-1537985011v1 cohort is administered a dose of 0.100 mg/kg of XmAb ® 27564 every 14 days for 4 doses (FIG.
  • FIG.3C depicts an open-label extension phase using XmAb ® 27564.
  • FIG.4 depicts a figure showing Tregs role in homeostasis and autoimmune diseases.
  • FIG.5 depicts XmAb ® 27564 engineered to improve selectivity for Treg.
  • FIGS.6A-6D depict XmAb ® 27564 designed to reduce potency and improve Treg selectivity.
  • FIG.6A In vitro stimulation of human PBMCs with either XmAb ® 27564 (FIG.6A) or Fc- WT-IL-2 (FIG.6B) revealed approximately 400-fold potency reduction for IL-2 signaling in human Tregs (phosphorylated STAT5 induction), with enhanced Treg selectivity over Tcons, gamma delta T cells, or NK cells.
  • the Treg EC50 is 21nM in FIG.6A and 0.06nM in FIG.6B.
  • FIGS.6C-6D depict a comparison of pharmacological half–life in cynomolgus macaques showing prolonged exposure of low-potency XmAb ® 27564 vs. WT Fc-IL-2.
  • FIG.7 depicts XmAb ® 27564 Phase 1a study design in healthy subjects.
  • FIG.7 shows a randomized and double-blinded Phase 1a single-ascending dose (SAD) study.
  • SAD Phase 1a single-ascending dose
  • the outcome measures were: 1) safety and tolerability and 2) pharmacokinetics and activity biomarkers (e.g., T-cell populations).
  • FIGS.8A-8B depict graphs showing that XmAb ® 27564 promotes robust and durable expansion of CD25 bright Tregs.
  • FIG.8B The numeric values in FIG.8B are the mean values. Peak fold change is the peak CD25 bright FoxP3 + CD4 Treg cell absolute count at a post-treatment time point divided by absolute count at baseline. NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test.
  • FIGS.9A-9B depict graphs showing that XmAb ® 27564 promotes robust and durable increase in CD25 bright Tregs/Tcon ratio.
  • the numeric values in FIG.9B are the mean values.
  • the dashed horizontal middle line represents the average of pre-dose values from all 48 subjects with ⁇ 2SD shown in grey lines above and below the middle dashed line.
  • FIGS.10A-10C depict graphs showing Treg responses after a single subcutaneous dose of XmAb ® 27564 in healthy subjects.
  • FIGS.10A-10B show that XmAb ® 27564 promotes robust and durable expansion of total Treg cells.
  • the numeric values in FIGS.10A-10C are the mean values. Peak fold change is the peak CD25+FoxP3+ CD4 Treg cell absolute count at a - 8 - NAI-1537985011v1 post-treatment time point divided by absolute count at baseline.
  • FIG.10C depicts a graph showing CD25 bright Treg cells (functionally highly immunosuppressive Tregs) after a single subcutaneous dose of XmAb ® 27564 in healthy subjects.
  • FIGS.11A-11B depict graphs showing that CD25 bright and total Treg remain elevated for at least three weeks following administration of XmAb ® 27564.
  • the numeric values in FIGS. 11A-11B are the mean values.
  • FIGS.12A-12D depict graphs showing Tcon (CD4 Tcon and CD8 Tcon) and NK cells (CD56+ and CD56bright NK cells) after a single subcutaneous dose of XmAb ® 27564.
  • FIGS.12A-12C depict graphs showing that XmAb ® 27564 induces minimal increases in conventional T cells and NK cells.
  • FIG.12A is directed to CD4 + Tcon cell count;
  • FIG.12B is directed to CD8 + Tcon cell count; and
  • FIG.12C is directed to CD56 + NK cell count.
  • FIG.12D depicts a graph showing CD25 bright NK cells after a single subcutaneous dose of XmAb ® 27564.
  • FIGS.12A-12D included: placebo, 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, and 0.065 mg/kg of XmAb ® 27564. Dashed horizontal middle line represent the average of pre-dose values from all 48 subjects with ⁇ 2SD shown in grey lines above and below the middle horizontal dashed line.
  • FIGS.13A-13B depict graphs showing that peak fold induction of CD25 bright and total Treg cells showed consistent dose response of Treg populations to XmAb ® 27564.
  • FIG. 13A shows Treg peak fold induction
  • FIG.13B shows total Treg peak fold induction.
  • FIGS.13A-13B are the mean values.
  • NS p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test.
  • FIGS.14A-14B depict graphs showing that ratio of CD25 bright /Tcon and total Treg/Tcon peak fold induction showed consistent dose response of Treg populations to - 9 - NAI-1537985011v1 XmAb ® 27564.
  • FIG.14A shows CD25 bright Treg/Tcon peak fold induction (CD25 hi FoxP3 + CD4 + ) and FIG.14B shows total Treg/Tcon peak fold induction (CD25 + FoxP3 + CD4 + ).
  • the numeric values in FIGS.14A-14B are the mean values.
  • NS p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test.
  • FIG.15 depicts a graph showing pharmacokinetics data after cohorts were injected with 0.003 mg/kg, 0.007 mg/kg, 0.015 mg/kg, 0.025 mg/kg, 0.04 mg/kg, or 0.065 mg/kg of XmAb ® 27564.
  • FIGS.16A-16B depict pharmacodynamics data.
  • FIG.16B shows selective and durable expansion and activation of Tregs through Day 21. *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 by Wilcoxon test to compare median from 564-treated group to placebo-treated group.
  • FIGS.17A-17F depict Treg (FIGS.17A-17B), Tcon (FIGS.17C-17D), and NK cells (FIGS.17E-17F) responses after a single subcutaneous dose of XmAb ® 27564 in healthy volunteers.
  • FIGS.18A-18H depict graphs characterizing expanded Tregs after a single subcutaneous dose of XmAb ® 27564.
  • FIGS.19A-19B depict graphs showing that serum levels of IL-10 increased in a dose-dependent manner, and at the highest dose level of 0.065 mg/kg there was a 15-fold increase at Day 10 after treatment.
  • FIG.19B shows that a peak mean 16-fold increase was observed in a graph showing serum IL-10/IFN- ⁇ ratio.
  • FIG.20 depicts a graph showing induction of peripheral eosinophilia in adult healthy volunteers after a single subcutaneous dose of XmAb ® 27564.
  • FIG.21 depicts a graph showing that IL5 increased in normal healthy volunteers after a single subcutaneous dose of XmAb ® 27564. 4.
  • a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
  • the conjunctive term “and/or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and/or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the - 11 - NAI-1537985011v1 first. A third option refers to the applicability of the first and second elements together.
  • cycle refers to a specified period of time during which a treatment (e.g., an IL2-Fc fusion protein) is administered to a subject.
  • a treatment e.g., an IL2- Fc fusion protein
  • Fc When a treatment is administered to a subject for multiple cycles, the cycles can occur at regular intervals. For example, a cycle can be immediately followed by one or more additional cycles, or two or more cycles can be separated by a period without treatment.
  • the terms “Fc,” “Fc region,” or “Fc domain” as used herein refer to the polypeptide comprising the CH2-CH3 domains of an IgG molecule, and in some cases, inclusive of the hinge. In EU numbering for human IgG1, the CH2-CH3 domain comprises amino acids 231 to 447, and the hinge is 216 to 230. Thus, the definition of “Fc domain” includes both amino acids 231-447 (CH2-CH3) or 216-447 (hinge-CH2-CH3), or fragments thereof.
  • an “Fc fragment” in this context may contain fewer amino acids from either or both of the N- and C-termini but still retains the ability to form a dimer with another Fc domain or Fc fragment as can be detected using standard methods, generally based on size (e.g., non-denaturing chromatography, size exclusion chromatography, etc.)
  • Exemplary human IgG Fc domains that can be used herein include human IgG1, IgG2, or IgG4.
  • the terms “Fc variant” or “variant Fc” as used herein refer to a protein comprising an amino acid modification in an Fc domain.
  • the Fc variants of the present disclosure are defined according to the amino acid modifications that compose them.
  • N434S or 434S is an Fc variant with the substitution serine at position 434 relative to the parent Fc polypeptide, wherein the numbering is according to the EU index.
  • M428L/N434S defines an Fc variant with the substitutions M428L and N434S relative to the parent Fc polypeptide. It is noted that the order in which substitutions are provided is arbitrary, that is to say that, for example, 428L/434S is the same Fc variant as M428L/N434S, and so on.
  • the EU index or EU index as in Kabat or EU numbering scheme refers to the numbering of the EU antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, hereby entirely incorporated - 12 - NAI-1537985011v1 by reference.)
  • the modification can be an addition, deletion, or substitution. Substitutions can include naturally occurring amino acids and, in some cases, synthetic amino acids. Examples include U.S. Pat. No.6,586,207; WO 98/48032; WO 03/073238; US2004-0214988A1; WO 05/35727A2 WO 05/74524A2; J. W.
  • Fc fusion protein refers to a protein comprising an Fc region, generally linked (optionally through a linker moiety, which can be the hinge region of an IgG, such as IgG1) to a different protein, such as IL-2.
  • an IL-2 Fc fusion protein is a protein comprising an IL-2 (in this case, variant IL-2) and Fc domain. These generally have the structure IL-2-hinge-CH2-CH3.
  • two Fc domains can self- assemble to provide dimeric Fc fusion proteins.
  • nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same, when compared and aligned for maximum correspondence, as measured using one of the following sequence comparison algorithms or by visual inspection.
  • sequence comparison typically one sequence acts as a reference sequence, to which test sequences are compared.
  • sequence comparison algorithm test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated.
  • sequence comparison algorithm calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.
  • Sequence identity between two similar sequences can be measured by algorithms such as that of Smith, T.F. & Waterman, M.S. (1981) “Comparison of Biosequences,” Adv. Appl. Math.2:482 [local homology algorithm]; Needleman, S.B. & Wunsch, CD. (1970) “A General Method Applicable to the Search for Similarities in the Amino Acid Sequence of Two Proteins,” J. Mol. Biol.48:443 [homology alignment algorithm], Pearson, W.R. & Lipman, D.J.
  • BLAST and BLAST 2.0 algorithms are described in Altschul et al. (1990) J. Mol. Biol.215: 403-410 and Altschul et al. (1997) Nucleic Acids Res. 25: 3389-3402, respectively.
  • Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information.
  • This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra).
  • the BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment.
  • the BLASTP program uses as defaults a word length (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)).
  • the BLAST algorithm In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. Nat’l. Acad. Sci. USA 90:5873-5787 (1993)).
  • One measure of similarity provided - 14 - NAI-1537985011v1 by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance.
  • a 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 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.
  • isolated when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Ordinarily, an isolated polypeptide can be prepared by at least one purification step.
  • “Recombinant,” when used to describe the various polypeptides disclosed herein, means the polypeptides are generated using recombinant nucleic acid techniques in exogeneous host cells, and they can be isolated as well.
  • wild type or WT refer to an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations.
  • a WT protein has an amino acid sequence or a nucleotide sequence that has not been intentionally modified.
  • the terms “peptide,” “polypeptide,” or “protein” can refer to a molecule comprised of amino acids and can be recognized as a protein by those of skill in the art.
  • peptide polypeptide
  • protein protein
  • variant protein refers to a protein that differs from that of a parent protein by virtue of at least one amino acid modification.
  • Protein variant may refer to the protein itself, a composition comprising the protein, or the amino sequence that encodes it.
  • the protein variant has at least one amino acid modification compared to the parent protein, e.g., from about one to about seventy amino acid modifications, or from about one to about five amino add modifications compared to the parent.
  • the parent polypeptide for example an Fc parent - 15 - NAI-1537985011v1 polypeptide, is a human wild type sequence, such as the Fc region from human IgG1, IgG2, IgG3 or IgG4.
  • the parent polypeptide is human IL-2, the mature sequence of which is SEQ ID NO: 1.
  • he protein variant sequence herein can possess at least about 80% identity, at least about 90% identity, or at least about 95%, 98%, or 99% identity with a parent protein sequence.
  • Variant protein can refer to the variant protein itself, compositions comprising the protein variant, or the DNA sequence that encodes it [0059]
  • the term “linker” as used herein refers to a proteinaceous linker that is used to join two other protein domains (e.g., the variant IL-2 domain and the variant Fc domain). In some cases, the linker is a “domain linker”, used to link any two domains.
  • linker While any suitable linker can be used, many embodiments utilize a glycine-serine polymer, including for example (GS)n, (GSGGS)n (SEQ ID NO: 4), (GGGGS)n (SEQ ID NO: 5), and (GGGS)n (SEQ ID NO: 6), where n is an integer of at least one (and generally from 3 to 4 to 5) as well as any peptide sequence that allows for recombinant attachment of the two domains with sufficient length and flexibility to allow each domain to retain its biological function.
  • charged domain linkers can be used.
  • the hinge domain of the human IgG1 protein can also be a domain linker.
  • the terms “regulatory T cells” or “Tregs” as used herein refers to T cells that are CD3+/CD4+/CD8 ⁇ /CD25+/FOXP3+.
  • the terms “treat,” “treatment,” and “treating” refer to the reduction or amelioration or elimination of the progression, severity and/or effect associated with plaque psoriasis or atopic dermatitis, as described herein, or the improvement in the plaque psoriasis or atopic dermatitis, or the improvement in the disease associated with the plaque psoriasis or atopic dermatitis, or the increase in the immune system response of the human subject, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of the plaque psoriasis or atopic dermatitis described herein resulting from the administration of one or more therapies.
  • treating plaque psoriasis or atopic dermatitis involves administering the IL2-Fc fusion protein for a pre-specified period of time, discontinuing administration for another specific period of time, and resuming administration of the IL2-Fc fusion protein for yet another specific period of time.
  • treating plaque psoriasis or atopic dermatitis involves administering the IL2-Fc fusion protein until one of the treatment effects described herein is achieved, pausing administration of the IL2-Fc fusion - 16 - NAI-1537985011v1 protein while this treatment effect continues to be observed, and resuming administration of the IL2-Fc fusion protein if this treatment effect ceases to be observed.
  • plaque-type psoriasis refers to plaque-type psoriasis (or plaque psoriasis).
  • Plaque-type psoriasis (or plaque psoriasis) treatment can be determined by standardized response criteria specific to the disease, e.g., by assessing the Psoriasis Area and Severity Index (PASI) score, Body Surface Area (BSA), Investigator’s Global assessment of improvement (IGA), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI), and/or based on photographs of whole body or specific plaques.
  • Psoriasis Area and Severity Index Psoriasis Area and Severity Index (PASI) score, Body Surface Area (BSA), Investigator’s Global assessment of improvement (IGA),
  • atopic dermatitis refers to eczema, and/or a chronic (long-lasting) disease that causes inflammation, redness, and irritation of the skin.
  • Atopic dermatitis treatment can be determined by standardized response criteria specific to the disease, e.g., by assessing Eczema Area and Severity Index (EASI), Body Surface Area (BSA), validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD), Peak Pruritis Numerical Rating Scale (PP-NRS), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI), and/or based on photographs of body.
  • EASI Eczema Area and Severity Index
  • BSA Body Surface Area
  • vIGA-AD validated Investigator Global Assessment for Atopic Dermatitis
  • Treatment according to the present invention includes a “therapeutically effective amount” of the medicaments used.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • a therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the medicaments to elicit a desired response in the individual. Alternatively, this property of a composition may be evaluated by examining the ability of the compound to inhibit cell growth or to induce apoptosis by in vitro assays known to the skilled practitioner.
  • a therapeutically effective amount can ameliorate at least one symptom in a subject.
  • a “therapeutically effective amount” refers to an amount of an IL-2 Fc fusion protein of the disclosure that is effective, upon single or multiple dose administration to a subject (such as a human patient) at treating, preventing, curing, delaying, reducing the severity of, ameliorating at least one symptom of a disorder (e.g., plaque psoriasis or atopic - 17 - NAI-1537985011v1 dermatitis) or recurring disorder, or prolonging the survival of the subject beyond that expected in the absence of such treatment.
  • a disorder e.g., plaque psoriasis or atopic - 17 - NAI-1537985011v1 dermatitis
  • One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject’s size, the severity of the subject’s symptoms, and the particular composition or route of administration selected.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the IL-2 Fc fusion protein can be incorporated into pharmaceutical compositions suitable for administration to a subject according to a dosage regimen described herein.
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564) and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are physiologically compatible and are suitable for administration to a subject using the methods described herein.
  • Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as any combination thereof.
  • isotonic agents can be included, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffers (such as an organic acid, which as a citrate or an acetate), which enhance the shelf life or effectiveness of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffers (such as an organic acid, which as a citrate or an acetate), which enhance the shelf life or effectiveness of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents (such as a polysorbate), preservatives or buffer
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564) and histidine. In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564) and sorbitol. In some embodiments, the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564), histidine (or a comparable agent), and sorbitol (or a comparable agent).
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564), 20 mM histidine (or a comparable agent), and 250 mM sorbitol (or a comparable agent), and the pH is 6.5.
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564), between about 10 mM and about 40 mM histidine (or a comparable agent), and between about 100 mM and about 400 mM sorbitol (or a comparable agent).
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564), between about 15 mM and about 25 mM histidine (or a comparable agent), and between about 200 mM and about 300 mM sorbitol (or a comparable agent).
  • the pharmaceutical composition comprises an IL-2 Fc fusion protein (e.g., XmAb ® 27564), between about 17 mM and about 23 mM histidine (or a comparable agent), and between about 240 mM and about 250 mM sorbitol (or a comparable agent).
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 1mL to 10 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 1mL to 30 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 10 mL vial (e.g., glass vial) or syringe.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 5 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 2 mL vial (e.g., glass vial) or syringe. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is packaged in a 1 mL vial (e.g., glass vial) or syringe.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a vial in each vial (e.g., glass vial), or in a syringe.
  • between about 15 mg and about 50 mg of an IL-2 Fc fusion protein is in a vial, in each vial (e.g., glass vial), or in a syringe.
  • between about 20 mg and about 40 mg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is in a vial, in each vial (e.g., glass vial), or in a syringe. In some embodiments, between about 25 mg and about 35 mg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is in a vial, in each vial (e.g., glass vial), or in a - 19 - NAI-1537985011v1 syringe.
  • about 30 mg/mL of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is in a vial, in each vial (e.g., glass vial), or in a syringe. In some embodiments, between about 15 mg/mL and about 50 mg/mL of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is in a vial, in each vial (e.g., glass vial), or in a syringe.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • between about 20 mg/mL and about 40 mg/mL of an IL-2 Fc fusion protein is in a vial, in each vial (e.g., glass vial), or in a syringe.
  • between about 25 mg/mL and about 35 mg/mL of an IL-2 Fc fusion protein is in a vial, in each vial (e.g., glass vial), or in a syringe.
  • the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is stored or shipped at a temperature of about 2° to about 8°C.
  • the vial with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is a single use vial.
  • the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is a sterile liquid supplied in a single use vial.
  • the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is supplied as a sterile liquid for injection. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is lyophilized. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is provided as an aqueous solution. In some embodiments, the pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is suitable for subcutaneous administration.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the pharmaceutical composition comprising an IL-2 Fc fusion protein is prepared by mixing an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of a desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (e.g., as outlined in Remington’s Pharmaceutical Sciences, 16th edition, Osol, A. editor [1980]) for storage as a lyophilized formulation or as an aqueous solution.
  • the pharmaceutical compositions can be in a variety of forms. These include, for example, liquid, lyophilized, liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions.
  • compositions are in the form of subcutaneous solutions.
  • Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • Sterile injectable solutions can be prepared by incorporating the IL- - 20 - NAI-1537985011v1 2 Fc fusion protein in the required amount in an appropriate solvent with one or any combination of ingredients enumerated herein, as required, followed by filtered sterilization.
  • An IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the route/mode of administration is subcutaneous injection. The route and/or mode of administration can vary depending upon the desired results.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is administered subcutaneously. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is administered until non-efficacy is determined, an unacceptable level of toxicity is observed, or is terminated (whether voluntarily or involuntarily) by the human subject. [0073] In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is a front line therapy, second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy.
  • a medical professional can readily determine and prescribe the effective amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) composition required.
  • a physician could start doses of the medicament employed in an IL-2 Fc fusion protein (e.g., XmAb ® 27564) composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • IL2-Fc Fusion Proteins Provided herein is a method of treating plaque psoriasis or atopic dermatitis in a subject with an IL-2 Fc fusion protein of the disclosure.
  • an IL-2 Fc fusion protein of the disclosure has three different domains: a Fc domain, one or more domain linkers, and an IL-2 domain.
  • an IL-2 Fc fusion protein of the disclosure is a heterodimeric monovalent construct, in which a variant IL-2 domain is generally fused to a variant human IgG Fc domain using either the hinge as the domain linker (generally including a C220S variant) or using an additional linker attached to the hinge, with the other Fc domain (including the hinge) remaining “empty”.
  • monovalent IL-2-Fc with linker comprises IL-2 (or variant IL-2) recombinantly fused to the N-terminus of a heterodimeric Fc- region via a domain linker, with the other side of the molecule being “Fc-only” or “empty-Fc”.
  • an IL-2 Fc fusion protein of the disclosure is a homodimeric bivalent construct, in which variant IL-2 domains are generally each fused to a variant human IgG1 Fc domain using either the hinge as the domain linker (generally including a C220S variant) or - 21 - NAI-1537985011v1 using an additional linker attached to the hinge.
  • bivalent IL-2-Fc with linker comprises IL-2 (or a variant IL-2) recombinantly fused to the N-terminus of both sides of a homodimeric Fc-region via a domain linker.
  • the domain linker is the IGG1 hinge, and in others it can include a linker selected from (GS)n, (GSGGS)n (SEQ ID NO: 4), (GGGGS)n (SEQ ID NO: 5), and (GGGS)n (SEQ ID NO: 6), where n is an integer of at least one.
  • an IL-2 Fc fusion protein of the disclosure is a heterodimeric protein complex comprising a first protein monomer comprising an IL-2 protein (e.g., a variant IL-2 protein) covalently linked to a first Fc domain (e.g., a first variant Fc domain) and a second protein monomer comprising a second Fc domain (e.g., a second variant Fc domain).
  • an IL-2 Fc fusion protein of the disclosure comprises an IL-2 protein consisting of an amino acid sequence of SEQ ID NO: 1.
  • an IL-2 Fc fusion protein of the disclosure comprises a variant human IL-2 protein (as compared to SEQ ID NO: 1).
  • an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence that is about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to a wild-type IL-2 protein (e.g., SEQ ID NO: 1).
  • an IL-2 Fc fusion protein of the disclosure comprises amino acid substitution(s) as compared to a wild-type IL-2 protein (e.g., SEQ ID NO: 1) selected from T3A, D20N, T37R, N71K, T3A/D20N, T3A/D20N/T37R and T3A/D20N/N71K.
  • a first monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises SEQ ID NO: 2.
  • a second monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises SEQ ID NO: 3.
  • a first monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 2.
  • a first monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 2 and comprises one or more mutation(s) selected from C220S, S267K, L368D, K370S, M428L, and/or N434S (variant Fc domain).
  • a second monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, - 22 - NAI-1537985011v1 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 3.
  • a second monomer or chain of an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 3 and comprises one or more mutation(s) selected from C220S, S267K, S364K, E357Q, M428L, and/or N434S (variant Fc domain).
  • a first monomer or chain of an IL-2 Fc fusion protein of the disclosure consists of an amino acid sequence of SEQ ID NO: 2.
  • a second monomer or chain of an IL-2 Fc fusion protein of the disclosure consists of an amino acid sequence of SEQ ID NO: 3.
  • a monomer (e.g., first monomer) or chain of an IL-2 Fc fusion protein of the disclosure comprises at least one of C220S, S267K, L368D, K370S, M428L, and N434S (compared to human IgG1 Fc domain).
  • a monomer (e.g., second monomer) or chain of an IL-2 Fc fusion protein of the disclosure comprises at least one of C220S, S267K, S364K, E357Q, M428L, and N434S (compared to human IgG1 Fc domain).
  • an IL-2 Fc fusion protein of the disclosure consists of: an amino acid sequence of SEQ ID NO: 1, an amino acid sequence of SEQ ID NO: 2, and an amino acid sequence of SEQ ID NO: 3.
  • an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about or at least about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to: SEQ ID NO: 1, SEQ ID NO: 2, and/or SEQ ID NO: 3.
  • N- and/or C-terminal clipping can occur during protein synthesis, whereby the heavy chains depicted herein may have the C-terminal lysine removed, as well as the penultimate glycine, and optionally additional amino acids residues (e.g., from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more C-terminal amino acids can be removed).
  • an IL-2 Fc fusion protein of the disclosure is XmAb ® 27564.
  • an IL-2 Fc fusion protein of the disclosure comprises an amino acid sequence comprising about, at least about, or at most about 70%, 75%, 80%, 90%, 91%, 91%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to any amino acid sequence in Table 1.
  • - 23 - NAI-1537985011v1 an IL-2 Fc fusion protein of the disclosure is a biosimilar of an IL-2 Fc fusion protein provided in Table 1.
  • an IL-2 Fc fusion protein of the disclosure is a biobeter of an IL-2 Fc fusion protein provided in Table 1.
  • an IL-2 Fc fusion protein of the disclosure is a bioequivalent of an IL-2 Fc fusion protein provided in Table 1. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a biosimilar of XmAb ® 27564. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a biobeter of XmAb ® 27564. In some embodiments, an IL-2 Fc fusion protein of the disclosure is a bioequivalent of XmAb ® 27564. Table 1.
  • an IL-2 Fc fusion protein of the disclosure comprises an Fc domain that comprises an ablation variant.
  • the normal binding of the Fc domain to one or more or all of the Fc ⁇ receptors is reduced or eliminated to avoid additional mechanisms of action.
  • ablation variants can be independently and optionally included or excluded.
  • an ablation variant includes, but is not limited to, C236R/L328R, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G, and E233P/L234V/L235A/G236del.
  • an IL-2 Fc fusion protein of the disclosure has a variant Fc domain that is a variant human IgG1 Fc domain comprising at least one amino acid substitution from E233P, L234V, L235A, G236del, and S267K (ablation variant).
  • the ablation variants of the disclosure ablate Fc ⁇ R binding but generally not FcRn binding.
  • an IL-2 Fc fusion protein of the disclosure is any IL-2 variant or IL-2 Fc fusion protein disclosed in WO2019125732 (PCT/US2018/063443) (the content of which is herein incorporated by reference in its entirety).
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a method for treating plaque psoriasis or atopic dermatitis in a human subject in need thereof comprising administering to the subject an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure, wherein the subject is first administered a first dose of the an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure on day 1, and subsequently administered a second dose of the an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure about 2 weeks after the first dose and at regular intervals (e.g., every 2 weeks) thereafter.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the first dose and the second dose is the same.
  • a method for treating plaque psoriasis or atopic dermatitis in a human subject in need thereof comprising administering to the subject an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as a single dose administration.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a method of the disclosure is used in a subject who has previously been treated for plaque psoriasis or atopic dermatitis.
  • a method of the disclosure is used in a subject who has not been previously treated for plaque psoriasis or atopic dermatitis (e.g., a na ⁇ ve subject).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein of the disclosure e.g., XmAb ® 27564
  • the subject does not have or has not been diagnosed with another type of psoriasis or atopic dermatitis, does not have or has not been diagnosed with another inflammatory condition (besides plaque psoriasis or atopic dermatitis), and/or does not have or has not been diagnosed with another dermatologic condition (besides plaque psoriasis or atopic dermatitis).
  • provided herein is a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) as a monotherapy treatment.
  • an IL-2 Fc fusion protein of the disclosure e.g., XmAb ® 27564
  • provided herein is a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) as a monotherapy treatment for plaque psoriasis or atopic dermatitis and at least one additional agent to treat or ameliorate at least one side effect of the IL-2 Fc fusion protein (e.g., XmAb ® 27564) administration or injection site in the subject.
  • an IL-2 Fc fusion protein of the disclosure e.g., XmAb ® 27564
  • provided herein is a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) as a monotherapy treatment for plaque psoriasis or atopic dermatitis and at least one additional agent to treat or ameliorate at least one symptom associated with the IL-2 Fc fusion protein (e.g., XmAb ® 27564) treatment.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • provided herein is a method of treating a subject diagnosed with or suspected of having severe plaque psoriasis or severe atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564). In some embodiments, provided herein is a method of treating a subject diagnosed with or suspected of having moderate plaque psoriasis or moderate atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb®27564).
  • provided herein is a method of treating a subject diagnosed with or suspected of having mild plaque psoriasis or mild atopic dermatitis with an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564).
  • an IL-2 Fc fusion protein of the disclosure e.g., XmAb ® 27564.
  • a method of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • an additional agent to treat at least one side effect or at least one symptom associated with plaque psoriasis and/or atopic dermatitis and/or the IL-2 Fc fusion protein (e.g., XmAb ® 27564) treatment.
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • Plaque psoriasis is an immune-mediated disease that causes raised, scaly patches on the skin due to systemic inflammation. In some embodiments, plaque psoriasis is triggered by at least one environmental factor. [0085] In some embodiments, the plaque psoriasis is chronic plaque psoriasis or chronic plaque-type psoriasis. In some embodiments, the plaque psoriasis is relapsing plaque psoriasis. In some embodiments, the plaque psoriasis is relapsing remitting plaque psoriasis. In some embodiments, the plaque psoriasis is non responsive to other plaque psoriasis treatment.
  • the plaque psoriasis is on the elbow(s) of the subject. In some embodiments, the plaque psoriasis is on the knee(s) of the subject. In some embodiments, the plaque psoriasis is on the scalp of the subject. In some embodiments, the plaque psoriasis is on the torso of the subject. [0086] In some embodiments, symptoms of plaque psoriasis include, but are not limited to, red or purple skin, itchy patches, shiny patches, and/or scaly skin. In some embodiments, symptoms of plaque psoriasis include, but are not limited to, thickening (plaque elevation, induration), and scaling (desquamation).
  • symptoms of plaque psoriasis include, but are not limited to, psoriasis-related itching, flaking, peeling, cracking, pain, scaling, and redness. 4.4.2.
  • Atopic Dermatitis is an immune-mediated skin disease.
  • atopic dermatitis is referred to as eczema.
  • the clinical characteristics of atopic dermatitis vary depending on age, disease stage, race or ethnic group, and/or geographic location. Typical acute lesions are circumscribed patches of eczema and erythema, which is more frequently violaceous or even invisible in patients with darker skin.
  • the lesions are characterized by papules, papulovesicles, edema, crusting, and scaling with hyperpigmentation or hypopigmentation of lesions after healing.
  • Atopic dermatitis may have disease stages.
  • a patient with atopic dermatitis has an eczema-free interval.
  • a patient with atopic dermatitis use emollients.
  • a topical immunosuppressive therapy is used when eczema occurs (e.g., in addition to XmAb ® 27564).
  • a patient has not been previously treated with an atopic dermatitis treatment.
  • a patient has been previously treated with an atopic dermatitis treatment.
  • a patient has been treated with or is being treated with monoclonal anti- - 27 - NAI-1537985011v1 interleukin-4, anti-interleukin-13, and/or anti-interleukin-31 antibodies, phosphodiesterase-4 inhibitors, and/or Janus kinase (JAK) inhibitors.
  • JNK Janus kinase
  • Target Patient Population Provided herein are methods of treating a subject diagnosed with or suspected of having plaque psoriasis or atopic dermatitis with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject does not have any other type or form of psoriasis. In some embodiments, the subject does not have any other type or form of atopic dermatitis. In some embodiments, the subject does not have any other inflammatory or dermatological condition (besides the plaque psoriasis or atopic dermatitis treated with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the subject has or is suspected of having plaque psoriasis. In some embodiments, the subject has or is suspected of having chronic plaque-type psoriasis.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject has or is suspected of having plaque psoriasis on one or at least one part of the body. In some embodiments, the subject has or is suspected of having atopic dermatitis. In some embodiments, the subject has or is suspected of having chronic atopic dermatitis. In some embodiments, the subject has or is suspected of having atopic dermatitis on one or at least one part of the body. In some embodiments, the subject is a human subject. In some embodiments, the subject is a male human subject. In some embodiments, the subject is a female human subject. In some embodiments, the subject is a juvenile. In some embodiments, the subject is an adult. In some embodiments, the human subject is between 18 to 65 years of age.
  • the subject has been diagnosed with or is suspected of having plaque psoriasis or atopic dermatitis.
  • the subject has at least one symptom (e.g., psoriasis-related itching, atopic dermatitis-related itching, flaking, peeling, cracking, pain, scaling, and redness) related to plaque psoriasis or atopic dermatitis.
  • the subject is experiencing or has experienced at least one symptom associated with plaque psoriasis or atopic dermatitis, such as, red or purple skin, eczema, itchy patches, shiny patches, scaly skin, and/or thickening (plaque elevation, induration) of skin.
  • the subject is not experiencing a symptom related to plaque psoriasis or atopic dermatitis.
  • the subject had at least one episode of plaque psoriasis or atopic dermatitis.
  • the subject has mild plaque psoriasis or previously had mild plaque psoriasis.
  • the subject has moderate plaque psoriasis or previously had moderate plaque - 28 - NAI-1537985011v1 psoriasis. In some embodiments, the subject has severe plaque psoriasis or previously had severe plaque psoriasis. In some embodiments, severity of plaque psoriasis is determined based on the PASI scoring system. In some embodiments, severity of plaque psoriasis is determined based on the body surface area (BSA), Investigator’s Global Assessment (IGA) score, or any suitable assessment, assay, or scoring system (e.g., as disclosed in Section 4.4.8 of the disclosure).
  • BSA body surface area
  • IGA Global Assessment
  • the subject has mild atopic dermatitis or previously had mild atopic dermatitis. In some embodiments, the subject has moderate atopic dermatitis or previously had moderate atopic dermatitis. In some embodiments, the subject has severe atopic dermatitis or previously had severe atopic dermatitis. In some embodiments, severity of atopic dermatitis is determined based on the EASI scoring system. In some embodiments, severity of atopic dermatitis is determined based on the body surface area (BSA), vIGA-AD, or any suitable assessment, assay, or scoring system used for atopic dermatitis.
  • BSA body surface area
  • the subject has a relapse of plaque psoriasis or atopic dermatitis. In some embodiments, the subject has refractory plaque psoriasis. In some embodiments, the subject has chronic relapsing plaque psoriasis. In some embodiments, the subject is unresponsive to at least one treatment for plaque psoriasis. In some embodiments, the subject is unresponsive to several treatments for plaque psoriasis (e.g., unresponsive to several biologics). In some embodiments, the subject has refractory atopic dermatitis. In some embodiments, the subject has chronic relapsing atopic dermatitis.
  • the subject is unresponsive to at least one treatment for atopic dermatitis. In some embodiments, the subject is unresponsive to several treatments for atopic dermatitis (e.g., unresponsive to several biologics). [0091] In some embodiments, the subject has at least one risk factor associated with plaque psoriasis or atopic dermatitis (e.g., smoking, obesity or overweight, elevated body mass index (BMI), use of certain medications, infection, use of alcohol, vitamin D deficiency, stress, skin irritation or any injury to the skin).
  • BMI body mass index
  • the subject has been previously treated with an agent for plaque psoriasis or atopic dermatitis (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment).
  • an agent for plaque psoriasis or atopic dermatitis e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment.
  • the subject has been previously treated with a treatment for plaque psoriasis or atopic dermatitis (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical - 29 - NAI-1537985011v1 treatment) within the last 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days
  • the subject is a na ⁇ ve subject (i.e., has not previously undergone treatment for plaque psoriasis or atopic dermatitis).
  • the subject has been previously treated with only one agent or only one treatment regimen for plaque psoriasis or atopic dermatitis.
  • the subject has been previously treated with at least one agent or with at least one treatment regimen for plaque psoriasis or atopic dermatitis.
  • the subject has been previously treated with two or more agents or two or more treatment regimens for plaque psoriasis or atopic dermatitis.
  • the subject has not been previously treated with a plaque psoriasis or atopic dermatitis agent or treatment (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment) within about or within the last 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days,
  • the subject has not been previously treated with a plaque psoriasis or atopic dermatitis agent or treatment (e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment) within about 30 days prior to treatment or first administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure to the subject.
  • a plaque psoriasis or atopic dermatitis agent or treatment e.g., systemic treatment, oral treatment, localized treatment, biologic treatment, phototherapy, or topical treatment
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject has not been previously treated with any agent or any treatment regimen for plaque psoriasis or atopic dermatitis.
  • the subject has not been previously treated with two or more agents or two or more treatment regimens for plaque psoriasis or atopic dermatitis.
  • the subject has not previously been administered an oral treatment for plaque psoriasis or atopic dermatitis in the 4 weeks prior to the administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject has not previously been administered a topical treatment for plaque psoriasis or atopic dermatitis in the 2 weeks prior to the administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject has not previously been administered a phototherapy in the 4 weeks prior to the administration of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL- 2 Fc fusion protein e.g., XmAb ® 27564
  • the subject has not previously been administered a biologic treatment for plaque psoriasis or atopic dermatitis for 12 weeks or 5 half-lives, whichever is longer, prior to the administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. 4.4.4.
  • a dose has a specific amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure that is administered to a subject over a defined time period.
  • the amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure administered to a subject is also known as the dose amount.
  • the time over which the dose amount is administered to a subject is also known as the administration time.
  • the dosage may be determined based upon the weight of the subject, such as by multiplying the weight (in kg, for example) of the subject by a dose amount - 31 - NAI-1537985011v1 (such as those described herein).
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject as a single dose.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject as part of a treatment cycle.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject more than once.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject at predetermined intervals.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is about, at least about, or at most about 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45 mg, 1.5 mg, 1.55 mg, 1.6 mg, 1.65 mg, 1.7 mg, 1.75 mg, 1.8 mg, 1.85 mg, 1.9 mg, 1.95 mg, 2 mg, 2.1 mg, 2.
  • a dose of an IL-2 Fc fusion protein is about, at least about, or at most about 0.001 mg/kg, 0.002 mg/kg, 0.003 mg/kg, - 32 - NAI-1537985011v1 0.004 mg/kg, 0.005 mg/kg, 0.006 mg/kg, 0.007 mg/kg, 0.008 mg/kg, 0.009 mg/kg, 0.010 mg/kg, 0.011 mg/kg, 0.012 mg/kg, 0.013 mg/kg, 0.014 mg/kg, 0.015 mg/kg, 0.016 mg/kg, 0.017 mg/kg, 0.018 mg/kg, 0.019 mg/kg, 0.020 mg/kb, 0.021 mg/kg, 0.022 mg/kg, 0.023 mg/kg, 0.024 mg/kg, 0.025 mg/kg, 0.026 mg/kg, 0.027 mg/kg
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is between about 0.001 mg/kg and about 0.150 mg/kg, between about 0.003 mg/kg and about 0.120 mg/kg, between about 0.005 mg/kg and about 0.02 mg/kg, between about 0.005 mg/kg and about 0.0270 mg/kg, between about 0.005 mg/kg and about 0.025 mg/kg, between about 0.003 mg/kg and about 0.007 mg/kg, between about 0.003 mg/kg and about 0.1 mg/kg, between about 0.002 mg/kg and about 0.008 mg/kg, between about 0.005 mg/kg and about 0.045 mg/kg, between about 0.005 mg/kg and about 0.050 mg/kg, between about 0.005 mg/kg and about 0.070 mg/kg, between about 0.005 mg/kg and about 0.15 mg/kg, between about 0.005 mg/kg and about 0.1 mg/
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is between about 0.003 mg/kg and about 0.12 mg/kg, 0.007 mg/kg and about 0.100 mg/kg, between about 0.006 mg/kg and about 0.020 mg/kg, between about 0.006 mg/kg and about 0.030 mg/kg, between about 0.006 mg/kg and about 0.040 mg/kg, between about 0.006 - 33 - NAI-1537985011v1 mg/kg and about 0.06 mg/kg, between about 0.006 mg/kg and about 0.070 mg/kg, 0.006 mg/kg and about 0.08 mg/kg, 0.006 mg/kg and about 0.090 mg/kg, 0.006 mg/kg and about 0.100 mg/kg, between about 0.006 mg/kg and about 0.120 mg/kg, between about 0.010 mg/kg and about 0.020 mg/kg, between about 0.010 mg/kg and
  • a method of treating plaque psoriasis or atopic dermatitis in a subject comprising subcutaneously administering to the subject a single dose of an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564).
  • a single dose of an IL-2 Fc fusion protein of the disclosure includes any dosage of the disclosure.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of about 0.003 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.003 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.007 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.007 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.015 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.015 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.025 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of 0.025 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.04 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.04 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.065 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.065 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of about 0.1 mg/kg. In certain embodiments, an - 35 - NAI-1537985011v1 IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of 0.1 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of between about 0.002 mg/kg to about 0.1 mg/kg, between about 0.003 mg/kg to about 0.07 mg/kg, between about 0.003 mg/kg to about 0.065 mg/kg, between about 0.002 mg/kg to about 0.004 mg/kg, between about 0.006 mg/kg to about 0.008 mg/kg, between about 0.010 mg/kg to about 0.020 mg/kg, between about 0.020 mg/kg to about 0.030 mg/kg, between about 0.030 mg/kg to about 0.050 mg/kg, between about 0.060 mg/kg to about 0.070 mg/kg, between about 0.050 mg/kg to about 0.080 mg/kg, between about 0.040 to about 0.07 mg/kg, or between about 0.060 to about 0.1 mg/kg.
  • XmAb ® 27564 is administered at a single dose of between about 0.002 mg/kg to about 0.1 mg/kg, between about 0.00
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of at least about 0.003 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at most about 0.003 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at least about 0.007 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of at most about 0.007 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at least about 0.015 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at most about 0.015 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of at least about 0.025 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at most about 0.025 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at least about 0.04 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure is administered at a single dose of at most about 0.04 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at least about 0.065 mg/kg. In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at most about 0.065 mg/kg.
  • an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at least about 0.1 mg/kg. - 36 - NAI-1537985011v1 In certain embodiments, an IL-2 Fc fusion protein of the disclosure (e.g., XmAb ® 27564) is administered at a single dose of at most about 0.1 mg/kg. [00102] In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject as a single dose.
  • a dose (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for 1 dose or 1 cycle, 2 doses or 2 cycles, 3 doses or 3 cycles, 4 doses or 4 cycles, 5 doses or 5 cycles, 6 doses or 6 cycles, 7 doses or 7 cycles, 8 doses or 8 cycles, 9 doses or 9 cycles, 10 doses or 10 cycles, 15 doses or 15 cycles, 20 doses or 20 cycles, 25 doses or 25 cycles, 30 doses or 30 cycles, 35 doses or 35 cycles, 40 doses or 40 cycles, 45 doses or 45 cycles, 50 doses or 50 cycles, 100 doses or 100 cycles, or more than 100 doses or 100 cycles.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a dose is administered about every 2 weeks.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered every 12, 13, 14, 15, 16, or 17 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered about or every 12 to 17 days, 13 to 17 days, 14 to 17 days, 15 to 17 days, 16 to 17 days, 12 to 16 days, 13 to 16 days, 14 to 16 days, 15 to 16 days, 12 to 15 days, 13 to 15 days, or 14 to 15 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered about every 25, 26, 27, 28, 29, 30, 31, or 32 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered about or every 22 to 32 days, 25 to 31 days, 26 to 31 days, 27 to 31 days, 28 to 31 days, 29 to 31 days, 30 to 31 days, 25 to 31 days, 26 to 30 days, 27 to 30 days, 28 to 30 days, 29 to 30 days, 28 to 30 days, or 29 to 30 days.
  • a dose of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered monthly (or once per month). In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered twice per month. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered every four weeks. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered every two weeks.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered twice a month or three times a month.
  • a cycle is about 12, 13, 14, 15, 16, or 17 days.
  • a cycle is about 25, 26, 27, 28, 29, 30, 31, or 32 days.
  • a cycle is about two weeks.
  • a cycle is about four weeks.
  • one cycle comprises administration of one dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • a dose is the same as an earlier dose and/or a subsequent dose. In some embodiments, a dose in a cycle is the same from an earlier dose and/or subsequent dose in a different cycle. In some embodiments, the number of cycles or doses varies based on the plaque psoriasis or atopic dermatitis of the subject. In some embodiments, the number of cycles or doses varies based on the treatment regimen for the plaque psoriasis or atopic dermatitis in the subject.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a subject e.g., every two weeks or every four weeks.
  • about, at least about, or at most about 0.007 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks).
  • about, at least about, or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks). In some embodiments, about, at least about, or at most about 0.025 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks).
  • about, at least about, or at most about 0.040 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks). In some embodiments, about, at least about, or at most about 0.065 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject (e.g., every two weeks, and for about, e.g., four doses; or every four weeks).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a subject e.g., every two weeks, and for about, e.g., four doses; or every four weeks.
  • a dose amount (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for about, at least about, or at most about: one dose, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200 doses or cycles, or more than 200 doses or cycles).
  • the subsequent dose is the same as the first dose or earlier dose.
  • a first dose amount e.g., - 38 - NAI-1537985011v1 between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a second dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a first dose amount (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject
  • a second dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a third dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject.
  • a first dose amount (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject
  • a second dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a third dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a fourth dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject.
  • more than four doses e.g., between about 0.003 mg/kg and about 0.2 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure are administered to a subject.
  • a fifth dose and/or any subsequent dose e.g., between about 0.003 mg/kg and about 0.2 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is/are administered to a subject.
  • a dose or a subsequent dose is administered about 2 weeks after a previous dose (e.g., the second dose is administered about 2 weeks after the administration of the first dose).
  • a dose or a subsequent dose is administered about 4 weeks after a previous dose (e.g., the second dose is administered about 4 weeks after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered about 13-15 days after a previous dose (e.g., the second dose is administered about 13-15 days after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered about 14 days after a previous dose (e.g., the second dose is administered about 14 days after the administration of the first dose).
  • a dose or a subsequent dose is administered about 27-31 days after a previous dose (e.g., the second dose is administered about - 39 - NAI-1537985011v1 24-31 days after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered about 24, 25, 26, 27, 28, 29, 30, or 31 days after a previous dose (e.g., the second dose is administered about 24, 25, 26, 27, 28, 29, 30, or 31 days after the administration of the first dose). In some embodiments, a dose or a subsequent dose is administered every four weeks (e.g., 24-31 days; or about 24, 25, 26, 27, 28, 29, 30, or 31 days).
  • a subsequent dose e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200 doses, or more than 200 doses; e.g., between about 0.003 mg/kg and about 0.2 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a dose amount (e.g., between about 0.005 mg/kg and about 0.009 mg/kg, or about 0.007 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a dose amount (e.g., between about 0.010 mg/kg and about 0.020 mg/kg, or about 0.015 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a dose amount (e.g., between about 0.020 mg/kg and about 0.030 mg/kg, or about 0.025 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a dose amount (e.g., between about 0.035 mg/kg and about 0.045 mg/kg, or about 0.40 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a dose amount (e.g., between about 0.06 mg/kg and about 0.07 mg/kg, or about 0.065 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a dose amount (e.g., between about 0.095 mg/kg and about 0.15 mg/kg, or about 0.1 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for a period of time (e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a period of time e.g., for 4 doses; e.g., every two weeks (or every 13-16 days; or every 14 days); or every four weeks).
  • a subsequent dose (e.g., 5, 6, 7, 8, 9, and/or 10, or - 40 - NAI-1537985011v1 more than 10 doses) (e.g., between about 0.003 mg/kg and about 0.2 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject (e.g., after about 2 weeks from a previous dose; about 13-16 days after a previous dose; or about 14 days after a previous dose; or every four weeks).
  • a subsequent dose is the same as the previous dose.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for 4 doses (e.g., between about 0.003 mg/kg and about 0.2 mg/kg). In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject for more than 4 doses (e.g., between about 0.003 mg/kg and about 0.2 mg/kg).
  • a cycle includes one administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure to a subject (e.g., between about 0.003 mg/kg and about 0.2 mg/kg). In some embodiments, a cycle is about two weeks. In some embodiments, a cycle is about four weeks. [00107] In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 12 and about 17 days.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 13 and about 15 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 13-15 days.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 12 and about 16 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 12-16 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 14-16 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 13 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 13 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 14 days.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 14 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every two weeks.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every two weeks.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 13 and about 17 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 13-17 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 15 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 15 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 16 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 24 and about 32 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 27 and about 31 days.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 28-31 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 28 and about 30 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 24-32 days or 27-31 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 28-30 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 24, 25, 26, 27, 28, 29, 30, or 31 days.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 24, 25, 26, 27, 28, 29, or 30 days.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 24, 25, 26, 27, 28, 29, or 30 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every four weeks.
  • a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every four weeks.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once between about 24 and about 32 days or between about 27 and about 30 days.
  • a dose e.g., between about 0.003 mg/kg and about 0.15 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 27-30 days.
  • a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 28, 29, 30, or 31 days. In some embodiments, a dose (e.g., between about 0.003 mg/kg and about 0.15 mg/kg) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once every 28 or 30 days. In some embodiments, a dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered once about every 28, 29, 30, or 31 days.
  • a method of the disclosure comprises administration (e.g., subcutaneous) of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure to a subject.
  • administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is via subcutaneous administration.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject for a period of time. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject until plaque psoriasis or atopic dermatitis is treated.
  • the IL- - 43 - NAI-1537985011v1 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject until plaque psoriasis or atopic dermatitis is improved in the subject (e.g., improved based on at least one efficacy assessment or assay for plaque psoriasis or atopic dermatitis (e.g., Section 4.4.8 and Section 5 of the disclosure)).
  • administration of an IL-2 Fc fusion protein stops after a positive therapeutic response (e.g., based on at least one efficacy assessment or assay for plaque psoriasis or atopic dermatitis (e.g., Section 4.4.8 or Section 5 of the disclosure)) is achieved.
  • a positive therapeutic response is a therapeutic response that ameliorates at least one symptom of plaque psoriasis or atopic dermatitis and/or ameliorates the severity (e.g., severe to moderate or mild) of plaque psoriasis or atopic dermatitis in a subject after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure begins again once the positive therapeutic response diminishes or disappears.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject at the start of relapse from a prior plaque psoriasis or atopic dermatitis treatment.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject after the subject has undergone at least one treatment for plaque psoriasis or atopic dermatitis.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject after the subject has been diagnosed with plaque psoriasis or atopic dermatitis. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject in combination with at least one agent that ameliorates at least one symptom associated with plaque psoriaris or atopic dermatitis.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject in combination with at least one agent that ameliorates at least one symptom associated with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject as a single dose administration.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every 2 weeks.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every 4 weeks. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about, at - 44 - NAI-1537985011v1 least about, or at most about once a month, twice a month, three times a month. In some embodiments, the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about, at least about, or at most about every 12, 13, 14, 15, 16, or 17 days..
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about, at least about, or at most about every 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every 14 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every 24, 25, 26, 27, 28, 29, 30, or 31 days.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject every 12 to 17 days, 12 to 16 days, 12 to 15 days, 12 to 14 days, 13 to 15 days, 13 to 16 days, 13 to 17 days, 14 to 15 days, 14 to 16 days, 14 to 17 days, or any suitable time period.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every two weeks.
  • the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject every 24 to 32 days, 24 to 31 days, 24 to 30 days, 25 to 32 days, 26 to 31 days, 27 to 31 days, 27 to 30 days, 28 to 30 days, 29 to 30 days, 28 to 31 days, 28 to 30 days, or any suitable time period.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every four weeks. [00112]
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every 14 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every two weeks. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject about every four weeks. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject on Day 1, Day 15, Day 19, and/or Day 43.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject on Day 1, Day 15, Day 19, Day 43, and/or every 14 days thereafter or every 14 days until end of treatment.
  • treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure comprises about, at least about, or at most about, 4 doses (or cycles).
  • treatment with an IL-2 Fc fusion protein comprises about, at least about, or at most about, 1 dose (or cycle), 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, - 45 - NAI-1537985011v1 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 350, 400, 450, 500 doses (or cycles), or more than about 500 doses (or cycles).
  • 1 dose or cycle
  • each dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject every 12, 13, 14, 15, 16, or 17 days.
  • each dose of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject every 24, 25, 26, 27, 28, 29, 30, or 31 days.
  • a cycle is about 12, 13, 14, 15, 16, or 17 days.
  • a cycle is about 24, 25, 26, 27, 28, 29, 30, or 31 days.
  • each dose is administered to a subject every 12 to 17 days.
  • each dose is administered to a subject every 25 to 32 days.
  • each dose is administered to a subject every 14 days. In some embodiments, each dose is administered to a subject every 24, 25, 26, 27, 28, 29, 30, or 31. In some embodiments, each dose is administered to a subject every 13 to 15 days. In some embodiments, each dose is administered to a subject every 24 to 30 days, 24 to 31 days, 25 to 32, 27 to 31, or 28 to 30 days. In some embodiments, each cycle is 12 to 17 days. In some embodiments, each cycle is 14 days. In some embodiments, each cycle is 13 to 15 days. In some embodiments, a dose is administered every 2 weeks. In some embodiments, a cycle is about two weeks. In some embodiments, each cycle is 24 to 31 days or 26 to 31 days. In some embodiments, each cycle is 14 days.
  • each cycle is 24, 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, each cycle is 27 to 30 days. In some embodiments, a dose is administered every 4 weeks. In some embodiments, a cycle is about 4 weeks. 4.4.5.1 Subcutaneous administration [00113] In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject via a subcutaneous administration. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to the subject via a single dose subcutaneous administration. In some embodiments, the term “subcutaneous” infusion or injection is meant to encompass any method of transcutaneous delivery to a subject.
  • a needle device is inserted at a selected site within the body of a subject for subcutaneous delivery of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) to the subject.
  • a pharmaceutical composition comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is administered subcutaneously to the subject.
  • a solution comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564), histidine - 46 - NAI-1537985011v1 (e.g., 20 mM), and sorbitol (e.g., 250 mM) is subcutaneously administered to the subject.
  • the solution is a sterile liquid for injection and practically free of visible particulates.
  • a solution comprising an IL-2 Fc fusion protein (e.g., XmAb ® 27564) suitable for subcutaneous administration is provided in a vial or ampule.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is subcutaneously administered to a subject about every 2 weeks or every 2 weeks.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is subcutaneously administered to a subject every 12 to 17 days, 12 to 16 days, 12 to 15 days, 12 to 14 days, 13 to 17 days, 13 to 16 days, 13 to 15 days, 13 to 14 days, 14 to 17 days, 14 to 16 days, or 14 to 15 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is subcutaneously administered to a subject about every, at least every, or at most every: 12 days, 13 days, 14 days, 15 days, 16 days, or 17 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is subcutaneously administered to a subject every 22 to 32 days, 24 to 30 days, 25 to 31 days, 27 to 30 days, or 28 to 30 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is subcutaneously administered to a subject about every, at least every, or at most every: 24, 25, 26, 27, 28, 29, 30, 31, or 32 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is subcutaneously administered to a subject about every 14 days.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is subcutaneously administered to a subject about every 24, 25, 26, 27, 28, 29, or 30 days. In some embodiments, an IL-2 Fc fusion protein (e.g., XmAb ® 27564) is subcutaneously administered to a subject once in a month, twice in a month, or three times in a month. [00114] In some embodiments, an autoinjector is used for subcutaneous administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) to the subject.
  • an autoinjector is used for subcutaneous administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) to the subject.
  • a syringe is used for subcutaneous administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) to the subject.
  • a 27 gauge syringe is used to administer an IL-2 Fc fusion protein (e.g., XmAb ® 27564) to the subject.
  • a 25 gauge to 30 gauge syringe is used (e.g., to administer an IL-2 Fc fusion protein to the subject).
  • a 3/8 inches to 5/8 inches needle is used.
  • a prefilled syringe is used to administer an IL-2 Fc fusion protein to the subject.
  • the syringe is a 1 mL - 47 - NAI-1537985011v1 syringe. In some embodiments, a syringe is a 2 mL syringe. In some embodiments, a syringe is a 5 mL syringe. In some embodiments, the syringe is at most a 10 mL syringe. In some embodiments, the syringe is at most a 30 mL syringe. In some embodiments, subcutaneous injection is administered at a 45- to 90-degree angle. In some embodiments, the injection is administered in any suitable body part of a subject.
  • the injection is administered in the left upper lateral arm (deltoid). In some embodiments, the injection is administered in the right upper lateral arm (deltoid).
  • the injection site is marked with a small circle and date of injection to identify injection site and to monitor reaction(s). In some embodiments, the injection site is monitored for pain, tenderness, erythema and/or swelling (e.g., Example 1 and/or by using a Canfield photography system). In some embodiments, a subject is assessed for allergic and non-allergic injection-related reactions after a subcutaneous administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564.
  • a subject is assessed for adverse event (e.g., within about 6 hours) from the start of a subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • an adverse event is a sign and/or symptom associated with hypersensitivity/anaphylactic reaction (e.g., skin, gastrointestinal, respiratory, cardiovascular, and neurologic systems) from a subcutaneous injection.
  • an electrocardiogram (ECG) assessment is performed predose and/or after (e.g., about 4 hours after) a subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected prior to subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected after subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected about 30 minutes after subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564).
  • blood pressure, heart rate, body temperature, pulse oximetry, and/or respiratory rate is collected every 60 minutes for 4 hours after subcutaneous injection of an IL-2 Fc fusion protein (e.g., XmAb ® 27564). 4.4.6.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564.
  • Previous Treatment For Plaque Psoriasis or Atopic Dermatitis - 48 - NAI-1537985011v1 Provided herein is a method of treating plaque psoriasis or atopic dermatitis in a subject with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure, wherein the subject has been previously treated with a previous therapy or treatment for plaque psoriasis or atopic dermatitis that is not the IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the previous therapy or treatment for plaque psoriasis or atopic dermatitis includes one agent for treating plaque psoriasis or atopic dermatitis.
  • the previous therapy or treatment for plaque psoriasis or atopic dermatitis means that the subject has undergone one treatment regimen for plaque psoriasis or atopic dermatitis.
  • the previous therapy or treatment for plaque psoriasis or atopic dermatitis means at least one agent for treating plaque psoriasis or atopic dermatitis.
  • the previous therapy or treatment for plaque psoriasis or atopic dermatitis means that the subject has undergone at least one treatment regimen for plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy or treatment for plaque psoriasis or atopic dermatitis means two or at least two agents for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy or treatment for plaque psoriasis or atopic dermatitis means that the subject has undergone two or at least two treatment regimen for plaque psoriasis or atopic dermatitis.
  • the previous therapy is used to treat the plaque psoriasis or atopic dermatitis that an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is used to treat in the subject.
  • a method of the disclosure further comprises administering an additional agent for treating at least one side effect or symptom associated with IL-2 Fc fusion protein (e.g., XmAb ® 27564) treatment and/or associated with the previous therapy.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is one agent for treating plaque psoriasis or atopic dermatitis.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis are two or more agents for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy for treating plaque psoriasis or atopic dermatitis are three or more agents for treating plaque psoriasis or atopic dermatitis. In some embodiments, the previous therapy is administered prior to the administration with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. [00117] In some embodiments, a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a non-responder.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a responder.
  • a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a relapser.
  • a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a rebounder.
  • a subject who has undergone previous plaque psoriasis or atopic dermatitis treatment is a partial responder.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a topical therapy.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is phototherapy (UVB, PUVA).
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a biologic, such as efalizumab.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a biologic, such as an antagonist of TNF, IL-12/23, IL-23, and IL-17.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a non-biologic, such as cyclosporine.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a small molecule systemic therapy or small molecule immunomodulators, such as methotrexate, acitretin, apremilast, and cyclosporin.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is a systemic agent for plaque psoriasis or atopic dermatitis.
  • Examples of a systemic agent for treating plaque psoriasis or atopic dermatitis include, but are not limited to, methotrexate, cyclosporine, fumaric acid esters, acitretin, alefacept, adalimumab, efalizumab, etanercept, infliximab, golimumab and/or ustekinumab.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is secukinumab.
  • the previous therapy for treating plaque psoriasis or atopic dermatitis is adalimumab, alefacept, etanercept, infliximab, and/or ustekinumab.
  • a previous therapy for atopic dermatitis is a monoclonal anti- interleukin-4, -13, and -31 antibodies, phosphodiesterase-4 inhibitors, and Janus kinase (JAK) inhibitors.
  • a previous therapy for atopic dermatitis is a topical immunosuppressive therapy.
  • the previous therapy is an IL-17 binding molecule (e.g., an IL- 17 antibody, such as secukinumab), a topical therapy (over the counter, non-steroidal compounds and steroidal compound), phototherapy, and/or systemic treatment (e.g., with biologics or chemical entities).
  • an IL-17 binding molecule e.g., an IL- 17 antibody, such as secukinumab
  • a topical therapy over the counter, non-steroidal compounds and steroidal compound
  • phototherapy e.g., with biologics or chemical entities.
  • Non-limiting examples of topical agents include salicylic acid, coal tar, Dovonex ® (calcipotriene), Taclonex ® (calcipotriene and betamethasone dipropionate), Tazorec ® (tazarotene), pimecrolimus, castellani’s paint (Castederm), tacrolimus, Vectical ® (calcitriol), - 50 - NAI-1537985011v1 Zithranol-RR ® (anthralin), and topical steroids (e.g., corticosteroids).
  • Non-limiting examples of phototherapy include treatment with psoralen+UVA or treatment with UVB (with or without tar).
  • Non-limiting examples of phototherapy include retionoids such as Acitretin (Soriatane ® ), cyclosporine, methotrexate, Hydrea ® (hydroxyurea), isotretinoin, tildrakizumab, risankizumab, broadalumab, ixekizumab, mycophenolate mofetil, mycophenolic acid, sulfasalazine, 6- thioguanine, fumarates (e.g, dimethylfumarate and fumaric acid esters), azathioprine, corticosteroids, leflunomide, tacrolimus, T-cell blockers (such as Amevive ® (alefacept) and Raptiva ® (efalizumab), tumor necrosis factor-alpha (TNF-alpha) blockers (such as Enbrel ® (etanercept), Humira ® (adalimumab), Remicade ®
  • the previous therapy includes, but it is not limited to, apremilast, mometasome, voclosporin, Ketokonazol, Neuroskin Forte, recombinant human interleukin-10, voclosporin, VX-765, dovonex, MED-I545, fluphenazine decanoate, bimosiamose cream, doxycycline, vancomycin, AbGn168, Vitamin D3, RO5310074, fludarabine Calcipotriol and hydrocortisone (LEO 80190), LE80185 (Taclonex ® Scalp topical suspension/Xamiol ® gel), Focetria (Monovalent MF59-Adjuvanted vaccine, tgAAC94 gene therapy vector, Apremilast, Capsaicin, Psirelax, ABT-874 (anti IL-12), IDEC-114, MEDI-522, INCB018424 phosphate cream, LE29102, B
  • An IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure and at least one additional therapeutic agent (e.g., agent for treating a side effect) can be administered simultaneously, in the same or in separate compositions, or sequentially.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure can be administered first, and the additional agent can be administered second, or vice versa.
  • An IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure can be administered before the other treatment or agent, concurrently with the treatment, post-treatment, or during a positive therapeutic response to the disorder.
  • an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure and the one or more additional agents can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each agent used individually.
  • an additional agent is an agent that ameliorates at least one side effect associated with plaque psoriasis or atopic dermatitis or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject.
  • a steroid is administered to a subject.
  • a steroid is administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the steroid is administered in an amount between about 5 mg and about 30 mg.
  • the steroid described herein is administered in an amount between about 5 mg and about 25 mg.
  • the steroid is administered in an amount between about 5 mg and about 15 mg.
  • the steroid is administered in an amount between about 8 mg and about 12 mg.
  • the steroid is administered in an amount between about 10 mg and about 20 mg. In one embodiment, the steroid is administered in an amount of about 10 mg.
  • the steroid is administered in an amount of 10 mg. In one embodiment, the steroid is administered in an amount between about 18 mg and about 22 mg. In one embodiment, the steroid is administered in an amount of about 20 mg. In one embodiment, the steroid is administered in an amount of 20 mg. In one embodiment, the steroid is dexamethasone. In one embodiment, the steroid is dexamethasone and is administered in an amount between about 10 mg and about 20 mg. In one embodiment, the steroid is dexamethasone and is administered in an amount of about 10 mg. In one embodiment, the steroid is dexamethasone. In some embodiments, dexamethasone is administered intravenously.
  • the steroid is dexamethasone and is administered in an amount of about 20 mg. In one embodiment, the steroid is dexamethasone and is administered between about 45 minutes and 75 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the steroid is dexamethasone and is administered about 60 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the steroid is dexamethasone and is administered about 60 minutes before an administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • about 20 mg of dexamethasone is administered about 60 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, about 20 mg of dexamethasone is administered about 60 minutes before an administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, a corticosteroid is administered to a subject. [00126] In some embodiments, an antidiarrheal treatment (e.g., Imodium or an equivalent) is administered to a subject. In some embodiments, electrolytes is administered to a subject.
  • an antidiarrheal treatment e.g., Imodium or an equivalent
  • electrolytes is administered to a subject.
  • acetaminophen e.g., 650 mg orally
  • an antipyretic is administered to a subject.
  • - 53 - NAI-1537985011v1 an analgesic is administered to a subject.
  • diphenhydramine e.g., 25 to 50 mg intravenously or orally
  • an equivalent is administered to a subject for treating rash, pruritus, or other signs and/or symptoms of hypersensitivity (allergic) reaction.
  • tocilizumab e.g., 8 mg/kg IV over 1 hour
  • dexamethasone e.g., 10 to 20 mg IV
  • about 10 mg dexamethasone is administered to a subject.
  • pressors, fluids, oxygen, epinephrine, bronchodilators, ventilatory support, antipyretic, and/or analgesic is administered to a subject.
  • an antihistamine is administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the antihistamine is an H1 antagonist. In one embodiment, the H1 antagonist is a first generation H1 antagonist. In one embodiment, the antihistamine is an ethanolamine. In one embodiment, the ethanolamine is diphenhydramine, carbinoxamine, doxylamine, orphenadrine, bromazine, clemastine, dimenhydrinate, or any combination thereof. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the antihistamine is administered in an amount between about 20 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount between about 20 mg and 30 mg. In one embodiment, the antihistamine is administered in an amount of about 25 mg.
  • the antihistamine is administered in an amount of 25 mg. In one embodiment, the antihistamine is administered in an amount between about 40 mg and 60 mg. In one embodiment, the antihistamine is administered in an amount between about 45 mg and 55 mg. In one embodiment, the antihistamine is administered in an amount of about 50 mg. In one embodiment, the antihistamine is administered in an amount of 50 mg. In one embodiment, the antihistamine is diphenhydramine and the amount between about 20 mg and about 30 mg. In one embodiment, the antihistamine is diphenhydramine and the amount is about 25 mg.
  • the antihistamine is diphenhydramine and is administered between about 20 minutes and 70 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the antihistamine is diphenhydramine and is administered between about 30 minutes and 60 minutes before an IL- - 54 - NAI-1537985011v1 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • acetaminophen is administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, acetaminophen is administered in an amount between about 100 mg and 1000 mg.
  • acetaminophen is administered in an amount between about 400 mg and 600 mg. In one embodiment, acetaminophen is administered in an amount of about 500 mg. In one embodiment, acetaminophen is administered in an amount of 500 mg. In one embodiment, acetaminophen is administered in an amount between about 500 mg and 800 mg. In one embodiment, acetaminophen is administered in an amount between about 550 mg and 750 mg. In one embodiment, acetaminophen is administered in an amount between about 600 mg and 700 mg. In one embodiment, acetaminophen is administered in an amount of about 650 mg. In one embodiment, acetaminophen is administered in an amount of 650 mg. In one embodiment, acetaminophen is administered in an amount of 650 mg.
  • the acetaminophen is administered between about 15 minutes and about 45 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the acetaminophen is administered about 30 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, the acetaminophen is administered between about 60 minutes and about 30 minutes before an administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the acetaminophen is administered between about 60 minutes and about 30 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In one embodiment, about 650 mg of acetaminophen is administered about 30 minutes before each administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • a steroid, an H1 antagonist, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • dexamethasone, an H 1 antagonist, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a - 55 - NAI-1537985011v1 steroid, diphenhydramine, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • dexamethasone, diphenhydramine, and acetaminophen are administered prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • dexamethasone is administered in an amount of about 10 mg or about 20 mg
  • diphenhydramine is administered in an amount of about 25 mg to 50 mg
  • acetaminophen is administered in an amount of about 650 mg prior to or after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. 4.4.8.
  • response to treatment after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject can be determined based on at least one efficacy assessment or assay for plaque psoriasis or atopic dermatitis as disclosed herein.
  • treatment efficacy or assessment is determined for a method of the disclosure.
  • treatment efficacy or assessment is determined before and/or after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • any assay available for determining improvement or used for assessing plaque psoriasis or atopic dermatitis can be used with a method of the disclosure.
  • maximum response, partial response, improvement, lost improvement, start of relapse, etc. may be measured by any available scoring system for plaque psoriasis, e.g., physician’s assessed efficacy measures, such as Psoriasis Area an Severity Index (PASI), Body Surface Measurement (BSA), clinical signs score: Investigator’s Global assessment of improvement (IGA), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), or health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI)).
  • PPSI Psoriasis Area an Severity Index
  • BSA Body Surface Measurement
  • HRQOL health-related quality of life
  • maximum response, partial response, improvement, lost improvement, start of relapse, etc. may be measured by any available scoring system for atopic dermatitis, e.g., physician’s assessed efficacy measures, such as Eczema Area and Severity Index (EASI), Body Surface Measurement (BSA), clinical signs score: validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA-AD), patient’s assessed efficacy measures, such as improvement of symptom(s) (itchy skin, skin scaling, redness of skin, pain, and/or soreness), or health-related quality of life (HRQOL) improvement (e.g., Dermatology Life Quality Index (DLQI)).
  • EASI Eczema Area and Severity Index
  • BSA Body Surface Measurement
  • HRQOL health-related quality of life
  • DLQI Dermatology Life Quality Index
  • efficacy of treatment after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is administered to a subject - 56 - NAI-1537985011v1 can be determined based on the number of regulatory T cells (e.g., CD4+ regulatory T (Treg) cells), NK cells, and/or conventional T cells (e.g., CD4+ conventional T (Tcon) cells, CD8+ Tcon T cells, or all non-Treg cells).
  • regulatory T cells e.g., CD4+ regulatory T (Treg) cells
  • NK cells e.g., NK cells
  • conventional T cells e.g., CD4+ conventional T (Tcon) cells, CD8+ Tcon T cells, or all non-Treg cells.
  • treatment efficacy or assessment is determined by comparing the score or outcome from at least one of the assessments or assays of the disclosure after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline score or outcome taken before treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564); compared to the score or outcome taken from the subject at an earlier time point; and/or compared to the score or outcome taken from at least one subject with plaque psoriasis or atopic dermatitis).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • treatment efficacy or assessment is determined 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
  • 4.4.8.1 Increase in the number of regulatory T (Treg) cells [00132]
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on the number of Treg cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Treg cells is determined by flow cytometry.
  • a Treg cell is CD4+ Treg cell.
  • a Treg cell is CD4+ CD25high Foxp3+ Tregs.
  • a Treg cell is CD3+/CD4+/CD8 ⁇ /CD25+/FOXP3+.
  • the number of Treg cells can be assessed at any time before or after administration - 57 - NAI-1537985011v1 of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Treg cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Treg cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week. In some embodiments, an increase in the number of Treg cells is observed while no increase or no significant increase in the number of convention T cells is observed after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure In some embodiments, conventional T cells are all non-Treg cells.
  • an increase in the number of Treg cells is observed within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks,
  • administration or treatment with an IL-2 Fc fusion protein results in an increase in the number of Treg cells or the number of Treg cells in a population of cells in the subject as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the increase is an increase of about, at least about, or at most about, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, or more than 300% as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the increase is an increase of about, at least about, or at most about, 0.5 fold, 1 fold, 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 5 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, or more than 50 fold as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the increase is an increase of about, at least about, or at most about, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, or more than 100 fold as compared to a reference (e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., the number of Treg cells or the number of Treg cells in a population of cells before administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the
  • the number of Treg cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks,
  • the number of Treg cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Treg cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 5 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Treg cells is assessed on - 59 - NAI-1537985011v1 Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 12 post administration of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 15 e.g., predose
  • the number of Treg cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 17 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Treg cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start
  • the number of Treg cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 31 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counte
  • the number of Treg cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Treg cells is assessed on the last day of treatment (e.g., about Day 88).
  • the number of Treg cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Treg cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on the number of effector T (Teff) cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Teff cells is determined by flow cytometry.
  • the number of Teff cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Teff cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Teff cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a reference e.g., compared to the number of Teff cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure used in a method of the disclosure is an amount that does not result in an increase or a significant increase in the number of Teff cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to the number of Teff cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or - 61 - NAI-1537985011v1 standard deviation).
  • little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%.
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the number of Teff cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks
  • the number of Teff cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Teff cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 5 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Teff cells is assessed on - 62 - NAI-1537985011v1 Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 12 post administration of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of Teff cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 15 e.g., predose
  • the number of Teff cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 17 e.g. 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted
  • the number of Teff cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 31 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 33, Day 36, and/or Day 40 (e.g
  • the number of Teff cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of Teff cells is assessed on the last day of treatment (e.g., about Day 88).
  • the number of Teff cells is assessed after treatment with an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of Teff cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on the number of NK cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells is determined by flow cytometry.
  • the number of NK cells or the total number of NK cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or the total number of NK cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of NK cells or the total number of NK cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week. In some embodiments, the NK cells refers to CD45+CD3-CD56+ NK cells.
  • NK cells or total NK cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to the number of NK cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • an amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure used in a method of the disclosure is an amount that does not result in an increase or a significant increase in the number of NK cells or total NK cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to the number of NK cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., compared to the number of NK cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase - 64 - NAI-1537985011v1 that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or standard deviation).
  • little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%.
  • NK cells or total NK cells are observed within 1 day, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or longer than 24 weeks after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the number of NK cells or the total of NK cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week
  • the number of NK cells or total NK cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed on Day 5 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed on Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 12 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 8 post administration of an IL-2 Fc fusion protein
  • the number of NK cells or total NK cells is assessed on Day 12 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed on Day 15 (e.g., pre
  • the number of NK cells or total NK cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • the number of NK cells or total NK cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of NK cells or total NK cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • the number of NK cells or total NK cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on the last day of treatment (e.g., about Day 88).
  • Day 45 e.g. 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of NK cells or total NK cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counte
  • the number of NK cells or total NK cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of NK cells or total NK cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 - 66 - NAI-1537985011v1 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days,
  • an IL-2 Fc fusion protein
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on the number of CD4+ conventional T (Tcon) cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD4+ Tcon cells is determined by flow cytometry.
  • the number of CD4+ Tcon cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD4+ Tcon cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a reference e.g., compared to the number of CD4+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure used in a method of the disclosure is an amount that does not result in an increase or a significant increase in the number of CD4+ Tcon cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to the number of CD4+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., compared to the number of CD4+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or standard deviation).
  • little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%.
  • little or no increase or no significant increase in the number of CD4+ Tcon cells is observed within 1 day, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or longer than 24 weeks after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the number of CD4+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks,
  • the number of CD4+ Tcon cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 5 post administration of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL- 2 Fc fusion protein e.g., XmAb ® 27564
  • the number of CD4+ Tcon cells is assessed on Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 12 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD4+ Tcon cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD4+ Tcon cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 17 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 19, Day 22, and/or Day 26
  • the number of CD4+ Tcon cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 31 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 33, Day 36,
  • the number of CD4+ Tcon cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on the last day of treatment (e.g., about Day 88).
  • Day 45 e.g. 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD4+ Tcon cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an
  • the number of CD4+ Tcon cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the - 69 - NAI-1537985011v1 number of CD4+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days,
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on the number of CD8+ conventional T (Tcon) cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD8+ Tcon cells is determined by flow cytometry.
  • the number of CD8+ Tcon cells can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD8+ Tcon cells is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • a reference e.g., compared to the number of CD8+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an amount of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure used in a method of the disclosure is an amount that does not result in an increase or a significant increase in the number of CD8+ Tcon cells after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as - 70 - NAI-1537985011v1 compared to a reference (e.g., compared to the number of CD8+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • a reference e.g., compared to the number of CD8+ Tcon cells at baseline or before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the amount is about or at most about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the amount is between about 0.003 mg/kg to about 0.015 mg/kg of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, little or no increase or no significant increase is an increase that is not statistically significant. A person skilled in the art would be able to recognize a statistically significant increase based on knowledge in the field (e.g., based on p value or standard deviation).
  • little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In some embodiments, little or no increase or no significant increase is an increase of about or at most about 5%.
  • little or no increase or no significant increase in the number of CD8+ Tcon cells is observed within 1 day, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or longer than 24 weeks after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the number of CD8+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks,
  • the number of CD8+ Tcon cells is assessed before (e.g., Day 1, predose) administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed 48 hours (Day 3) post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 5 post administration of an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL- 2 Fc fusion protein e.g., XmAb ® 27564
  • the number of CD8+ Tcon cells is assessed on Day 8 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 12 post administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the number of CD8+ Tcon cells is assessed on Day 15 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the number of CD8+ Tcon cells is assessed on Day 17 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 19, Day 22, and/or Day 26 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 29 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 17 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 19, Day 22, and/or Day 26
  • the number of CD8+ Tcon cells is assessed on Day 31 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 33, Day 36, and/or Day 40 (e.g., counted from the start of treatment with an IL- 2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 43 (e.g., predose) before administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • Day 31 e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 33, Day 36,
  • the number of CD8+ Tcon cells is assessed on Day 45 (e.g., 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on the last day of treatment (e.g., about Day 88).
  • Day 45 e.g. 48 hours after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure). In some embodiments, the number of CD8+ Tcon cells is assessed on Day 47, Day 50, Day 54, and/or Day 57 (e.g., counted from the start of treatment with an
  • the number of CD8+ Tcon cells is assessed after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the number of CD8+ Tcon cells is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week, 2 weeks, 3 weeks, 4 days, 5 days
  • Psoriasis Area and Severity Index [00152]
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on a Psoriasis Area and Severity Index (PASI) score.
  • PASI Psoriasis Area and Severity Index
  • 4 main body areas are assessed: the head (h), the trunk (t), the upper extremities (u), and the lower extremities (l), corresponding to 10, 30, 20, and 40% of the total body area, respectively.
  • 3 target symptoms namely erythema (E), infiltration (I), and desquamation (D) are assessed according to a scale 0–4, where 0 means a complete lack of cutaneous involvement and 4 represents the severest possible involvement.
  • the severity rating for the 3 main target symptoms is multiplied with the numerical value of the areas involved and with the various percentages of the 4 body areas.
  • PASI 0.1 ⁇ Ah ⁇ (Eh + Ih + Dh) + 0.3 ⁇ At ⁇ (Et + It + Dt) + 0.2 ⁇ Au ⁇ (Eu + Iu + Du) + 0.4 ⁇ Al ⁇ (El + Il + Dl).
  • the index varies in steps of 0.1 units from 0.0 to - 73 - NAI-1537985011v1 72.0.
  • the PASI 50, 75, and 90 represent the fraction of patients that have improvement of the PASI score of 50%, 75% and 90% over the baseline PASI (Oji V, Luger TA.
  • PASI can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, PASI is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • PASI is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week.
  • the subject achieves an improvement in PASI score of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline PASI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to PASI score of other subjects with plaque psoriasis; and/or compared to PASI score of the same subject taken at an earlier time point).
  • an IL-2 Fc fusion protein e.g.,
  • the subject achieves an improvement in PASI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, -24, -25, -26, -27, -28, -29, or -30, for example, at about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days
  • the subject achieves a PASI 50, 75, 90, or 100 by about, or at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 85 days, 90 days, 95 days, 100 days
  • the subject achieves a PASI 50, 75, or 90 by 70 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50, 75, 90, or 100, by 60 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50, 75, 90, or 100, by 90 days or less (e.g., at 88 days or less) after administration (e.g., first administration, second administrations, or any - 75 - NAI-1537985011v1 administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50, 75, 90, or 100, by 100 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50, 75, 90, or 100, by 200 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50, 75, 90, or 100 before the end of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 75 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 50 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 90 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a PASI 100 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • PASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60
  • PASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 - 76 - NAI-1537985011v1 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1
  • EASI Eczema Area and Severity Index
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on Eczema Area and Severity Index (EASI) score.
  • EASI is assessed based on the area of involvement, intensity of lesions, region score, and final EASI score.
  • area of involvement includes four body regions, such as head and neck, upper extremities, trunk, and lower extremities.
  • an area score can be: 0 (no involvement), 1 (1%–9%), 2 (10%–29%), 3 (30%–49%), 4 (50%–69%), 5 (70%–89%), and 6 (90%–100%).
  • the intensity of lesions is assessed separately for 4 signs including erythema, edema/papulation, excoriation, and lichenification.
  • each sign is assigned an intensity score from 0 to 3, with 0 being absent; 1, mild; 2, moderate; and 3, severe.
  • each region is assigned based on the relative contribution of that region to the total BSA.
  • a region score is calculated separately for each region by multiplying the sum of the regional intensity score by the regional area score and the region-specific multiplier.
  • the final EASI score is the summation of the 4 regional scores, ranging from 0 to 72. A score of 0 indicates clear or no eczema, 0.1 to 1.0 indicates almost clear, 1.1 to 7 indicates mild disease, 7.1 to 21 indicates moderate disease, 21.1 to 50 indicates severe disease, and greater than 51 indicates very severe disease.
  • EASI can be assessed at any time before or after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, EASI is assessed about every 1 day, 2 days, 3 days, or 4 days after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, EASI is assessed about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, or 9 times a week.
  • the subject achieves an improvement in EASI score of about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline EASI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to EASI score of other subjects with atopic dermatitis; and/or compared to EASI score of the same subject taken at an earlier time point).
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject achieves an improvement in EASI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, - 24, -25, -26, -27, -28, -29, or -30, for example, at about or at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days
  • the subject achieves EASI 50, 75, 90, or 100 by about, or at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days,
  • the subject achieves a EASI 50, 75, or 90 by 70 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50, 75, 90, or 100, by 60 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50, 75, 90, or 100, by 90 days or less (e.g., at 88 days or less) after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50, 75, 90, or 100, by 100 days or less after administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50, 75, 90, or 100, by 200 days or less after - 79 - NAI-1537985011v1 administration (e.g., first administration, second administrations, or any administration) or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50, 75, 90, or 100 before the end of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 75 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 50 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the subject achieves a EASI 90 after (e.g., on Day 57) treatment or administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • EASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60
  • EASI is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 - 80 - NAI-1537985011v1 days, 110 days, 120 days, 130 days, 140 days, 150 days, 175 days, 200 days, 1 week
  • treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure results in improvement of at least one health-related quality of life (HRQOL) outcome (e.g., Dermatology Life Quality Index (DLQI)).
  • HRQOL health-related quality of life
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on DLQI.
  • DLQI is self-administered with a mean completion time of 2 min.
  • DLQI consists of 10 questions concerning impact of skin diseases on different aspects of subject’s quality of life (QOL) over, for example, the last week (e.g., 1 week after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure).
  • the DLQI items include symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the side effects of treatment (Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple practical measure for routine clinical use. Clin Exp Dermatol.1994;19:210–216).
  • the minimal clinically important difference of the DLQI varies from 3 to 5 (Basra MK, Salek MS, Camilleri L, et al. Determining the minimal clinically important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further data. Dermatology.2015;230(1):27–33).
  • the subject achieves a Dermatology Life Quality Index (DLQI) score of about 0 or 1 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • DLQI Dermatology Life Quality Index
  • the subject achieves a Dermatology Life Quality Index (DLQI) score of about or at most about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the - 81 - NAI-1537985011v1 disclosure.
  • the subject achieves an improvement in DLQI score of about or at least about -1 (i.e., a decrease of 1) after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline DLQI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to DLQI score of other subjects with plaque psoriasis or atopic dermatitis; and/or compared to DLQI score of the same subject taken at an earlier time point).
  • a reference e.g., compared to baseline DLQI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure
  • a reference e.g., compared to
  • the subject achieves an improvement in DLQI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, -23, - 24, -25, -26, -27, -28, -29, or -30 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline DLQI score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to DLQI score of other subjects with plaque psoriasis or atopic dermatitis; and/or compared to DLQI score of the same subject taken at an IL-2 F
  • the subject achieves an improvement in DLQI score of about or at least about -5 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference. In some embodiments, the subject achieves an improvement in DLQI score of about or at least about -7 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference. In some embodiments, the subject achieves an improvement in DLQI score of about or at least about -8 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the subject achieves an improvement in DLQI score of about or at least about -9 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference.
  • the subject achieves a clinically meaningful reduction in Dermatology Life Quality Index (DLQI) score.
  • DLQI Dermatology Life Quality Index
  • a clinically meaningful reduction in DLQI score is a decrease of 5 points or greater than 5 points in DLQI score compared to a reference.
  • a clinically meaningful reduction in DLQI score is a decrease of 3 points or greater than 3 points in DLQI score compared to a reference.
  • a clinically meaningful reduction in DLQI score is a decrease of 4 points or greater than 4 points in DLQI score compared to a reference.
  • the subject achieves an improvement in DLQI score at about or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 - 82 - NAI-1537985011v1 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline DLQI
  • the subject achieves an improvement in DLQI score of about or at least about -1, -2, -3, -4, -5, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, -21, -22, - 23, -24, -25, -26, -27, -28, -29, or -30 at about or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after treatment with an IL-2 Fc fusion protein (e.g.,
  • a reference is the baseline DLQI score obtained from the same subject prior to start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • a reference is the DLQI score obtained from the same subject at an earlier time point.
  • a reference is the DLQI score of at least one subject with plaque psoriasis or atopic dermatitis (e.g., an average DLQI score based on the DLQI scores from other subjects with plaque psoriasis or atopic dermatitis).
  • the at least one subject and/or the other subjects have the same plaque psoriasis or atopic dermatitis as the subject. In some embodiments, the at least one subject and/or the other subjects have the same plaque psoriasis or atopic dermatitis with the same level of severity (e.g., mild, moderate, or severe plaque psoriasis or atopic dermatitis) as the subject. In some - 83 - NAI-1537985011v1 embodiments, the at least one subject and/or the other subjects have been diagnosed with a different level of severity of plaque psoriasis or atopic dermatitis as the subject.
  • BSA body surface area
  • efficacy of treatment with an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • BSA Body Surface Area
  • the body surface area of plaque psoriasis is estimated by using the size of the handprint as 1% of the body surface area.
  • the number of handprints across the patient’s body that have activity with plaque psoriasis or atopic dermatitis is counted to determine BSA (Ramsay B, Lawrence CM. Measurement of involved surface area in patients with plaque psoriasis or atopic dermatitis. Br J Dermatol.1991;124(6):565–70).
  • BSA body surface area
  • the subject has a body surface area (BSA) of plaque psoriasis of ⁇ 3%.
  • the subject has a body surface area (BSA) of plaque psoriasis of ⁇ 2%.
  • the BSA is assessed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 days,
  • the BSA of the subject is decreased by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, or more than 300% after administration or treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline BSA score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to BSA score of other subjects with - 84 - NAI-1537985011v1 plaque psoriasis or atopic dermatitis; and/or compared to BSA score of the same subject taken at an earlier time point).
  • an IL-2 Fc fusion protein e.g.
  • the BSA of the subject is decreased after about or at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or longer than 24 months after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure as compared to a reference (e.g., compared to baseline BSA score of the subject, e.g., prior to treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure; compared to BSA score of other subjects with plaque psoriasis or atopic IL-2 Fc
  • the subject had about, less than about, or at most about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% body surface area (BSA) affected by plaque psoriasis or atopic dermatitis prior to administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • BSA body surface area
  • the subject has about, less than about, or at most about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% body surface area (BSA) affected by plaque psoriasis or atopic dermatitis after administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • BSA body surface area
  • efficacy of treatment with an IL-2 Fc fusion protein is assessed based on a Physician’s Global Assessment (PGA) test or an Investigator’s Global Assessment test (IGA) or a Static Investigator Global Assessment (sIGA) (Langley RG, Feldman SR, Nyirady J, et al.
  • the 5-point Investigator's Global Assessment (IGA) Scale A modified tool for evaluating plaque psoriasis severity in clinical trials.
  • efficacy of treatment with an IL-2 Fc fusion protein is assessed using - 85 - NAI-1537985011v1 Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) for atopic dermatitis.
  • the validated Investigator Global Assessment for Atopic Dermatitis is a static 5-point scale that was developed to assess the overall atopic dermatitis severity.
  • a score of 0 (clear) to 4 (severe) is provided based on a morphological description (refer to Table 17).
  • the IGA or sIGA is a 5- point system that measures severity of plaque psoriasis or atopic dermatitis.
  • the PGA is a 5 or 6 point scoring system used to assess severity of plaque psoriasis or atopic dermatitis in a subject.
  • the PGA or IGA or sIGA or vIGA-AD is about or at most about 2 (mild) after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure. In some embodiments, the PGA or IGA or sIGA or vIGA-AD is about or at most about 0 or 1 (clear, almost clear, or mild) after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • the PGA or IGA or sIGA or vIGA-AD is about or at most about 0 or 1 or 2 after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • the PGA or IGA or sIGA or vIGA-AD is about or at most about 0 or 1 by about or by at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 90 days, 95 days, 100 days, 110 days, 120 days, 130 days,
  • the PGA or IGA or sIGA or vIGA-AD is about or at most about 0, 1, 2, 3, after treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure (e.g., by about or by at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 - 86 - NAI-1537985011v1 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55
  • efficacy of treatment after an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed based on photography of whole body and/or selected plaques or active regions of atopic dermatitis (e.g., utilizing a Canfield photography system (Canfield Scientific, Parsippany, NJ)).
  • photographs e.g., of the whole body, selected plaques, or active regions of atopic dermatitis, or site of injection
  • an IL-2 Fc fusion protein e.g., XmAb ® 27564
  • photographs taken at baseline or before treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is compared with photographs taken after the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • photographs are taken at different time points after the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • photographs taken at a later time point after the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is compared with photographs taken at an earlier time point.
  • photographs are taken prior to the start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • photographs are taken at about or by at most about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 - 87 - NAI-1537985011v1 days, 31 day, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48 days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55 days, 56 days, 57 days, 58 days, 59 days, 60
  • photographs of injection site reactions are taken.
  • photographs e.g., of whole body, selected plaques, or active regions of atopic dermatitis, or site of injection
  • photographs are taken on day 1, 29, and/or 57.
  • photographs are taken prior to day 1 or prior to start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • photographs are taken about 7 days prior to start of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure.
  • pruritus is assessed using Peak Pruritus Numerical Rating Scale (e.g., for atopic dermatitis).
  • PP-NRS is an 11-point scale used by patients to rate their worst itch severity over the past 24 hours with 0 indicating “No itch” and 10 indicating “Worst itch imaginable”.
  • daily (24-hour) PP-NRS is recorded and the weekly mean of the daily PP-NRS is calculated.
  • PP-NRS scores are calculated between Day -7 and Day -1 and calculated a weekly average baseline score prior to Day 1.
  • efficacy of treatment with an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure is assessed by measuring specific cell populations (e.g., number of CD25 bright Treg cells, CD25 bright Treg/Tcon ratio, total Treg cells, conventional T cells (Tcon), - 88 - NAI-1537985011v1 and/or NK cells) in a subject before and/or after the IL-2 Fc fusion protein (e.g., XmAb®27564) of the disclosure is administered to the subject (e.g., number of CD25 bright Treg cells, CD25 bright Treg/Tcon ratio, total Treg cells, conventional T cells (Tcon), and/or NK cells).
  • specific cell populations e.g., number of CD25 bright Treg cells, CD25 bright Treg/Tcon ratio, total Treg cells, conventional T cells (Tcon), - 88 - NAI-1537985011v1 and/or NK cells
  • a method of the disclosure comprises a single administration of an IL-2 Fc fusion protein (e.g., XmAb ® 27564) of the disclosure to a subject.
  • cell population changes e.g., increases, decreases, or does not significantly increase or decrease
  • assessments are obtained on days -1, 0, 8, 10, 21, and/or 43, and/or at any suitable time point.
  • assessments are obtained on Day -1 (one day prior to administration of XmAb ® 27564 to the subject).
  • assessments are obtained on Day 0 (same day as administration of XmAb ® 27564 to the subject). In some embodiments, assessments are obtained on Day 8 (8 days after administration of XmAb ® 27564 to the subject). In some embodiments, assessments are obtained on Day 10 (10 days after administration of XmAb ® 27564 to the subject). In some embodiments, assessments are obtained on Day 21 (21 days after administration of XmAb ® 27564 to the subject). In some embodiments, assessments are obtained on Day 43 (43 days after administration of XmAb ® 27564 to the subject).
  • the CD25 bright Treg/Tcon ratio is about or at least about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, or more than 0.2. In some embodiments, the CD25 bright Treg/Tcon ratio is about 0.14 after administration of XmAb ® 27564.
  • administration of the IL-2 Fc fusion protein to a subject results in an increase in the number of CD25 bright Treg cells in the subject (e.g., biological sample) as compared to baseline or as compared to the number of CD25 bright Treg cells in the subject (e.g., biological sample) obtained from a previous time point.
  • administration of the IL-2 Fc fusion protein to a subject results in an increase in the number of CD25 bright Treg/Tcon ratio in the subject (e.g., biological sample) as compared to baseline or as compared to the number of CD25 bright Treg/Tcon ratio in the subject (e.g., biological sample) obtained from a previous time point.
  • administration of the IL-2 Fc fusion protein to a subject results in an increase in the number of total Treg cells in the subject (e.g., biological sample) as compared to baseline or as compared to the number of total Treg cells in the subject (e.g., biological sample) obtained from a previous time point.
  • Treg cells - 89 - NAI-1537985011v1 comprises CD25 bright FoxP3+ CD4 Treg cells.
  • Treg cells consists of CD25 bright FoxP3+ CD4 Treg cells.
  • the increase is an increase of about or at least about 2-fold, about or at least about 3-fold, about or at least about 4-fold, about or at least about 5-fold, about or at least about 6-fold, about or at least about 7-fold, about or at least about 8-fold, about or at least about 9-fold, about or at least about 10-fold, about or at least about 11- fold, about or at least about 12-fold, about or at least about 13-fold, about or at least about 14- fold, about or at least about 15-fold, about or at least about 16-fold, about or at least about 17- fold, about or at least about 18-fold, about or at least about 19-fold, about or at least about 20- fold, about or at least about 25-fold, about or at least about 30-fold, about or at least about 40- fold, about or at least about 50-fold, about or at least about 60-fold, about or at least about 70- fold, about or at least about 80-fold, about or at least about 90-fold, about or at least about 100- fold,
  • the increase is an increase of about or at least about 2%, about or at least about 3%, about or at least about 4%, about or at least about 5%, about or at least about 6%, about or at least about 7%, about or at least about 8%, about or at least about 9%, about or at least about 10%, about or at least about 11%, about or at least about 12%, about or at least about 13%, about or at least about 14%, about or at least about 15%, about or at least about 16%, about or at least about 17%, about or at least about 18%, about or at least about 19%, about or at least about 20%, about or at least about 25%, about or at least about 30%, about or at least about 35%, about or at least about 40%, about or at least about 45%, about or at least about 50%, about or at least about 55%, about or at least about 60%, about or at least about 65%, about or at least about 70%, about or at least about 75%, about or at least about 80%, about or at least about
  • a biological sample is blood, serum, plasma, and/or any other suitable biological sample.
  • administration of the IL-2 Fc fusion protein to a subject does not result in a significant increase in conventional T cells (Tcon) and/or NK cells in the subject as compared to baseline or as compared to the number of Tcon and/or NK cells obtained from the subject at a previous time point (e.g., in a biological sample obtained at a previous time point).
  • Tcon comprises of CD4 + Tcon cells.
  • Tcon - 90 - NAI-1537985011v1 comprises of CD8 + Tcon cells.
  • Tcon comprises of CD4 + and CD8 + Tcon cells.
  • Tcon consists of CD4 + Tcon cells. In some embodiments, Tcon consists of CD8 + Tcon cells. In some embodiments, Tcon consists of CD4 + and CD8 + Tcon cells. In some embodiments, a significant increase is not more than two standard deviations from baseline or those obtained from a previous time point. In some embodiments, a significant increase is not more than two standard deviations from baseline or those obtained from a previous time point. In some embodiments, a biological sample is blood, serum, plasma, and/or any other suitable biological sample. 5. EXAMPLES [00173] Examples are provided below to illustrate the present invention. These examples are not meant to constrain the present invention to any particular application or theory of operation.
  • EXAMPLE 1 Treatment of plaque psoriasis or atopic dermatitis using an IL-2 Fc fusion protein
  • XmAb ® 27564 is a potency-reduced monomeric human IL-2 Xtend heterodimeric Fc- fusion protein.
  • Xencor engineered XmAb ® 27564 IL-2 that decreases interactions with effector T cells (Teffs) and natural killer cells (NK cells), the largest cellular sink for IL-2, while preserving interactions with the autoimmune therapeutic target CD25, which is constitutively and highly expressed on Tregs.
  • recombinant IL-2 (rIL-2) was engineered to decrease interactions with cells containing predominantly complexes of IL2R ⁇ / ⁇ c (CD122/CD132; Teffs and NK cells) while simultaneously increasing affinity to the CD25 receptor thus preserving or increasing interactions for cells, such as Tregs, that express all 3 receptors IL2R ⁇ /IL2R ⁇ / ⁇ c (CD25/CD122/CD132).
  • Reduction of potency to CD122/CD132 resulted in increased serum persistence relative to the native IL-2 Fc fusion.
  • the dramatic increase in serum persistence - 91 - NAI-1537985011v1 offsets the significant reduction in potency, with a net increase in Tregs’ PD.
  • SC subcutaneous
  • HCV hepatitis C virus
  • SLE systemic lupus erythematosus
  • a single dose of ultra-low-dose IL-2 ( ⁇ 1.0 mIU) only induces a 10% to 20% increase in peripheral Treg numbers (Todd et al. PLOS Med.2016;13:e1002139), whereas daily dosing for 5 days can induce 2- to 8-fold expansion of Tregs (Table 2; Rosenzwajg et al. Ann Rheum Dis.2019;78:209–17).
  • the psoriasis cohorts consist of approximately 48 eligible adult (e.g., 18-65 years of age male and female) patients randomized to XmAb ® 27564 or placebo in 6 consecutive dose cohorts, 0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg (Cohorts 1 through 6). Each cohort consists of 8 patients with 6 patients receiving XmAb ® 27564 and 2 receiving placebo. Sentinel dosing can be employed for the first 3 patients in each cohort, with a block of 3 sentinel subjects, randomized 2:1 to XmAb ® 27564:placebo treated sequentially. Each sentinel subject in the same cohort is treated at least 24 hours after treatment of the previous sentinel subject.
  • the subsequent - 95 - NAI-1537985011v1 5 subjects to round out the 8-subject cohort are randomized 4:1 to XmAb ® 27564:placebo (4 XmAb ® 27564 and 1 placebo).
  • the subsequent 5 subjects may begin treatment after the third sentinel subject clears the first 24 hours.
  • the atopic dermatitis cohorts consist of approximately 80 eligible patients randomized to XmAb ® 27564 or placebo in 5 consecutive dose cohorts, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg (Cohorts A through E). Each cohort consists of 16 patients, with 12 patients receiving XmAb ® 27564 and 4 receiving placebo.
  • Each cohort in the psoriasis group consists of 8 patients, while each cohort in the atopic dermatitis group consists of 16 patients.
  • the increase in cohort size from 8 in the psoriasis cohorts to 16 in the atopic dermatitis cohorts is driven by the variability in the placebo response in skin assessments in atopic dermatitis.
  • Each patient either in the psoriasis or atopic dermatitis group
  • XmAb ® 27564 or placebo is administered in a double-blind fashion.
  • DERC Dose Escalation Review Committee
  • SAD single ascending dose
  • a DERC decision for escalation in a psoriasis cohort may trigger the start of dosing for an atopic dermatitis cohort at the same or lower dose studied previously for patients with psoriasis.
  • the DERC reviews Cohorts A through D and make a decision about dose escalation independently in atopic dermatitis based on safety considerations in atopic dermatitis.
  • placebo patients would also receive open-label XmAb ® 27564 at that cohort’s dose level. After each subsequent DERC meeting, all patients would be offered the higher dose that was cleared previously by the DERC for their disease population, at Investigator's discretion and upon consultation with the Medical Monitor.
  • the primary endpoint of the study is safety and tolerability of MAD SC administration of XmAb ® 27564, as measured by incidence of adverse events (AEs), including treatment-emergent AEs (TEAEs), treatment-emergent serious AEs (TE-SAEs), treatment- related TEAEs, treatment-related TE-SAEs, and TEAEs by severity that are defined by the National Cancer Institute’s Common Terminology Criteria for AEs (NCI-CTCAE), Version 5.0 (CTCAE v.5).
  • AEs adverse events
  • TEAEs treatment-emergent AEs
  • TE-SAEs treatment-emergent serious AEs
  • NCI-CTCAE Common Terminology Criteria for AEs
  • CTI-CTCAE Common Terminology Criteria for AEs
  • Safety assessments includes evaluating physical examinations, vital signs, electrocardiogram (e.g., twelve-lead ECG), dose-limiting toxicity (DLT), and clinical laboratory tests including clinical chemistry, hematology (including eosinophils), coagulation, troponin I CRP, ferritin, urinalysis, viral testing, and cardiac MRI.
  • the secondary endpoints of the study include characterizing PK and immunogenicity profiles of multiple-ascending doses (MAD) of XmAb ® 27564, including assessment of serum concentrations of XmAb ® 27564 and anti-XmAb ® 27564 antibodies (i.e., anti-drug antibodies (ADA) and immunogenicity).
  • MAD multiple-ascending doses
  • Subjects with psoriasis are randomized to XmAb ® 27564 or placebo in 6 consecutive dose cohorts, (i.e., 0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg every 14 days for four doses during 8 weeks of treatment), with 8 subjects in each cohort (6 subjects receive XmAb ® 27564 and 2 subjects receive placebo).
  • XmAb ® 27564 For patients with atopic dermatitis, 5 dose levels were selected for XmAb ® 27564: 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg, to be given Q14 days for four doses - 102 - NAI-1537985011v1 during 8 weeks of treatment. Each cohort has 16 patients; 12 patients are to receive XmAb ® 27564, and 4 patients are to receive placebo. [00188] Approximately 48 patients with psoriasis and 80 patients with atopic dermatitis receive XmAb ® 27564 or placebo at 20 to 25 clinical investigation sites in the US and outside of the US (OUS).
  • Approximately 96 patients receive XmAb ® 27564, and 32 patients in total receive placebo (12 psoriasis and 20 atopic dermatitis).
  • a total of 6 subjects receive XmAb ® 27564 and 2 subjects receive placebo.
  • the DERC may decide to either remove a planned cohort or add an unplanned cohort at a lower or intermediate dose level than planned. 5.1.3.
  • Treatment Assignment in the Open-Label Extension Phase Patients entering the OLE, receive active open label XmAb ® 27564 at the same dose level that was assigned to them in the core study, every 2 weeks. After each dose level has been reviewed by the DERC and is deemed safe, any patients who are receiving a lower dose of XmAb ® 27564 are offered the higher dose that was cleared by the DERC after discussion with the Investigator and upon consultation with the Medical Monitor. The increased dose is continued through the remainder of the extension phase, unless a new higher dose is cleared. 5.1.4. Treatment Assignment in the Core Study [00190] Randomization schedules for each dose cohort are generated prior to study start. XmAb ® 27564 or placebo are administered in a double-blind fashion.
  • Patient treatment assignment in patients with psoriasis includes MAD administration of SC XmAb ® 27564 (0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo.
  • Treatment assignment in patients with atopic dermatitis includes MAD administration of SC XmAb ® 27564 (0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo.
  • Sentinel dosing is employed for the first 3 patients with psoriasis in each cohort, with a block of 3 sentinel subjects, randomized 2:1 to XmAb ® 27564:placebo treated one each day sequentially with at least 24 hours between them (or over the first 3 days).
  • Each sentinel subject in the same cohort is treated at least 24 hours after treatment of the previous sentinel subject.
  • the subsequent 5 subjects to round out the 8-subject cohort are randomized 4:1 to XmAb ® 27564:placebo (4 XmAb ® 27564 and 1 placebo).
  • the subsequent 5 subjects begin treatment after the third sentinel subject clears the first 24 hours.
  • no sentinel dosing is employed for the atopic dermatitis - 103 - NAI-1537985011v1 cohorts.
  • a total of 16 patients are randomized in a 3:1 ratio to receive either XmAb ® 27564 or placebo in each cohort (FIG.3B).
  • the contract research organization maintain the randomization code in a secure location with controls to prevent unauthorized access, including the computer program written to generate the randomization, randomization codes, program log, seed number used by the program, copy of the randomization plan along with approval documentation as appropriate, and the write-protected electronic storage medium.
  • the CRO name an unblinded statistician to generate the randomization codes. The pharmacists are unblinded. Investigators and site staff, patients, CRO, and Xencor (excluding DAT) remain blinded to individual patients’ treatment assignment for the duration of the study until the study unblinding has been authorized.
  • Subject Inclusion Criteria - 104 - NAI-1537985011v1 [00197] In order to be eligible to participate in this study, an individual must meet all of the following criteria: Patients with psoriasis • Provision of signed and dated ICF • Stated willingness to comply with all study procedures and availability for the duration of the study • Male or female, aged 18 to 65 or 75 years of age (inclusive at the time of screening) • Weight between 40 to 150 kg, inclusive • BSA involved by psoriasis ⁇ 3% or ⁇ 2% • Static Investigator's Global Assessment (sIGA) of 2 (mild) - 4 (severe) • Washout of oral treatments for psoriasis for 4 weeks before randomization • Washout of biologic treatments for psoriasis for 12 weeks or 5 half-lives (whichever is longest) before randomization.
  • sIGA Static Investigator's Global Assessment
  • Highly effective methods of birth control include combined hormonal birth control (oral, intravaginal, or transdermal), or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or intrauterine), intrauterine devices (IUDs), intrauterine hormone-releasing system, - 105 - NAI-1537985011v1 bilateral tubal occlusion, vasectomized partner (provided partner is the sole sexual partner and there has been a medical assessment of surgical success), or sexual abstinence.
  • the baseline weekly average is calculated from the 7 consecutive days prior to Day 1 (between Day -7 and Day -1). A minimum of 4 daily scores out of the 7 days is needed.
  • Washout of oral treatments for atopic dermatitis for 4 weeks before randomization • Washout of biologic treatments for atopic dermatitis for 12 weeks or 5 half-lives (whichever is longest) before randomization - 106 - NAI-1537985011v1 • Washout of topical treatments for atopic dermatitis 2 weeks before randomization • Application of a stable dose of a non-prescription, non-urea containing emollient to all skin (normal skin and AD lesions) once or twice daily for 14 days preceding the randomization visit and willing to maintain stable dosing of the emollient from 14 days before randomization until at least the Day 57 visit • Washout for: ⁇ UV-B, PUVA, excimer laser, excessive sun for at least 4 weeks before randomization ⁇ IVIg for 12 weeks before randomization ⁇ Hydroxyzine or di
  • Female patients of childbearing potential must agree to use a highly effective method of birth control during and for 45 days after administration of IMP. Women are considered of childbearing potential or postmenopausal by history with no menses for 1 year and confirmed by FSH) or have a history of hysterectomy and/or bilateral oophorectomy or have a history of bilateral tubal ligation.
  • Highly effective methods of birth control include combined hormonal birth control (oral, intravaginal, or transdermal), or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or intrauterine), IUDs, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner (provided partner is the sole sexual partner and there has been a medical assessment of surgical success), or sexual abstinence.
  • hormonal birth control oral, intravaginal, or transdermal
  • progestogen-only hormonal contraception associated with inhibition of ovulation oral, injectable, or intrauterine
  • IUDs intrauterine hormone-releasing system
  • bilateral tubal occlusion bilateral tubal occlusion
  • vasectomized partner provided partner is the sole sexual partner and there has been a medical assessment of surgical success
  • sexual abstinence • Fertile male patients must be willing to practice a highly effective method of birth control during and for 45 days after administration of IMP with any female partners of childbearing potential. • Male patients
  • Patients have to be maintained on a medium dose inhaled corticosteroid plus a long-acting beta agonist as defined by GINA as a maximum • Patients who have evidence of any bacterial, viral, parasitic, or systemic fungal infections requiring treatment within the 21 days prior to randomization; or hospitalization due to infection within 3 months prior to randomization • Patients who do not agree to use medically acceptable methods of contraception (as defined in the protocol) • Patients who are pregnant or breast feeding, or planning to become pregnant within 45 days of administration of IMP • Patients who have had any prior investigational treatment with IL-2 therapies or have received any investigational agent within 5 half-lives of the study drug • Patients whose screening breathalyzer (for alcohol) and/or urine test is positive for drugs of abuse (including the following: amphetamines/ecstasy, barbiturates, benzodiazepines, cocaine, opiates, methadone metabolites, and phencyclidine).
  • drugs of abuse including the following: amphetamines/ecstasy, barb
  • results are positive or questionable, contact the Xencor Medical Monitor prior to enrollment • Patients with a known or suspected sensitivity to products from mammalian cell lines • Patients with a history of anaphylaxis • Patients who have received live vaccines ⁇ 2 months prior to screening or any vaccine within the past 14 days • Patients who have donated or lost more than 450 mL of blood in the 8 weeks prior to screening • Patients who have clinically significant abnormal laboratory values, as assessed by the Investigator or the Xencor Medical Monitor Patients with atopic dermatitis • Patients with history of any cardiovascular event, such as the following: heart failure, myocarditis, myocardial infarction, acute coronary syndrome, stroke, pulmonary embolism, and/or deep venous thrombosis • Patients with vital sign values outside these normal ranges: - 109 - NAI-1537985011v1 ⁇ Systolic Blood Pressure: 90–140 mmHg ⁇ Diastolic Blood Pressure: 50–90 mmHg ⁇ Heart Rate: 50–100 beats
  • Patients have to be maintained on a medium dose inhaled corticosteroid plus a long-acting beta agonist as defined by GINA as a maximum • Patients who have evidence of any bacterial, viral, parasitic, or systemic fungal infections requiring treatment within the 21 days prior to randomization; or hospitalization due to infection within 3 months prior to randomization • Patients who do not agree to use medically acceptable methods of contraception (as defined in the protocol) • Patients who are pregnant or breast feeding, or planning to become pregnant within 45 days of administration of IMP • Patients who have had any prior investigational treatment with IL-2 therapies or have received any investigational agent within 5 half-lives of the study drug • Patients whose screening breathalyzer (for alcohol) and/or urine test is positive for drugs of abuse (including the following: amphetamines/ecstasy, barbiturates, benzodiazepines, - 110 - NAI-1537985011v1 cocaine, opiates, methadone metabolites, and phencyclidine).
  • drugs of abuse including the following
  • results are positive or questionable, contact the Xencor Medical Monitor prior to enrollment.
  • Patients with a known or suspected sensitivity to products from mammalian cell lines • Patients with a history of anaphylaxis • Patients who have received live vaccines ⁇ 2 months prior to screening or any vaccine within the past 14 days • Patients who have donated or lost more than 450 mL of blood in the 8 weeks prior to screening • Patients who have clinically significant abnormal laboratory values, as assessed by the Investigator or Xencor Medical Monitor 5.1.5.3 Additional Subject Exclusion Criteria [00199] Patients must be withdrawn if the ⁇ -HCG pregnancy test is consistent with pregnancy. Pregnancy should be reported. [00200] Patients are encouraged to complete all study evaluations; however, they may withdraw from the study at any time and for any reason.
  • Patient participation may be terminated prior to completing the study and the reason recorded as follows: • Withdrawal from the study with or without withdrawing of consent • Administrative decision by the Investigator or Sponsor • Ineligibility • Significant protocol deviation • Patient noncompliance • Safety concern by the Investigator or Sponsor • Lost to follow-up • Other - 111 - NAI-1537985011v1 [00202] A comprehensive effort must be made to determine the reason(s) why a patient fails to return for the necessary visits or is discontinued from the study. If the patient is unreachable by email or telephone, a registered letter, at the minimum, should be sent to the patient requesting him/her to contact the study site. Patients withdrawn for a non-drug-related reason may be replaced if the Sponsor deems it necessary.
  • lymphopenia Patients with persistent (multiple measures at ⁇ 1000 lymphocytes/ ⁇ L and 75% below their baseline for more than 2 months after the last dose) or severe lymphopenia ( ⁇ 500 lymphocytes/ ⁇ L and > 75% below baseline) shall be referred to a primary care physician for treatment.
  • a patient withdraws prematurely all assessments as listed for the EOS visit should be performed and recorded on the EOS visit electronic case report form (eCRF) page.
  • the patient should be scheduled for follow-up safety visits (or after 5 half-lives, whichever is longer) after XmAb ® 27564 administration.
  • EOS patients Any patient who withdraws early who is lymphopenic on the last visit prior to withdrawal or at post-EOS visits is followed as with other EOS patients, every 28 days ( ⁇ 3 days). Patients are evaluated with CBC with differential, immunoglobulin levels, IL-2 levels and ADA, if feasible, until ADA levels return to baseline and after DERC review. Patients with persistent ( ⁇ 1000 lymphocytes/ ⁇ L for more than 2 months) or severe lymphopenia ( ⁇ 500 lymphocytes/ ⁇ L) (FDA, 2007) shall be referred to a primary care physician for treatment. 5.1.6. Dosing Schedule [00206] Each subject receives subcutaneous administration of XmAb ® 27564 or placebo every 2 weeks for 4 doses, as shown in FIGS.3A-3B.
  • XmAb ® 27564 or placebo is administered on - 112 - NAI-1537985011v1 Study Days 1, 15, 29, and 43. Up to 6 weeks screening and a follow up period of approximately 45 days may be used. Possible injection areas include upper arm, thigh, or abdomen. Injection administration is not at the same place twice. The area rotates from one dose to the next. [00207] Open-label Extension: Up to 336 days duration; follow-up period of approximately 45 days (FIG.3C). All patients who rollover into the extension phase of the study initially receive open-label XmAb ® 27564 every 2 weeks at the dose level of the cohort that they were assigned to during the core study.
  • Treatment Assignment will include MAD administration of SC XmAb27564 (0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo. [00211] Detail of treatment assignment, including randomization and blinding, is presented below. 5.1.9.
  • Advancement to subsequent cohorts will depend on acceptable interim safety, available immunogenicity, PK, and PD reviews from ongoing and completed cohorts. Advancement to a subsequent dose level will not occur until at least 8 patients from the prior - 113 - NAI-1537985011v1 dose level have each been administered investigational medicinal product (IMP) without safety concerns.
  • IMP investigational medicinal product
  • a DERC will be established to assess all available and relevant interim data from each cohort to determine the safety and appropriateness of dose reduction to a prior or intermediate dose or dose escalation to a new cohort. Dose escalation will follow pre-specified criteria.
  • the maximum tolerated dose will be defined by the dose in the previous cohort, unless an intermediate dose is subsequently tested by the same algorithm.
  • More conservative dose escalation i.e., evaluation of prior or intermediate dose levels, is permissible following DERC review, if needed, for patient safety or for a better understanding of the toxicity, exposure, PD, or other properties of the study drug.
  • the Sponsor may decide to add a cohort to repeat a dose level, but the dose level for any cohort will not exceed the planned dose level for that cohort, as specified in this protocol, below.
  • DAT Data Analysis Team
  • the blinded DERC will also include Xencor’s blinded Medical Monitor, Xencor’s blinded Head of Hematology, Clinical Development (or their designees), the Coordinating Principal Investigator (or Designee), and the CROs Safety Monitor (or designee), who will be responsible for all single-patient and administrative study discussions and decisions.
  • the blinded DERC will receive deidentified data in real time, enabling a prompt and effective - 114 - NAI-1537985011v1 response to safety and study administrative issues.
  • Voting DERC members will include 4 physicians: the Coordinating Principal Investigator, CROs Safety Monitor or their designees, and 2 from Xencor (blinded Medical Monitor and blinded Head of Hematology, Clinical Development or their designees).
  • DERC meetings are timed to review all blinded PD, PK, immunogenicity, and safety data before escalation to the next cohort. Progression to the next higher dose will only occur if the DERC determines that the previous dose level was safe and well tolerated after reviewing all patients’ data collected through at least Day 29. When it is not appropriate to escalate the dose, then the same dose, a previous dose, or an intermediate dose may be recommended by the DERC.
  • the DERC and DAT will have access to information relating to XmAb27564 clinical data in their deliberations regarding dose escalation in this study.
  • the dose escalation process, DERC and DAT function and personnel, and data to be reviewed will be described in a DERC Charter document, to be provided separately.
  • Dose Adjustment Criteria 5.1.11.1 Treatment Group Stopping Rules and Dose Level Adjustments [00220] Upon review of pooled cohort data by the DERC, following the final dose of the last patient in the previously completed cohort, dose escalation to the next higher-dose cohort may proceed upon review, confirmation, and documentation of acceptable interim safety, PK, and PD findings from all available interim data.
  • DLTs dose escalation will not proceed, if any of the following criteria (DLTs) are met: - 115 - NAI-1537985011v1
  • DLTs drug-related myocarditis resulting in a reduction in ejection fraction by cardiac MRI.
  • SAEs from placebo arm will be assessed as not related to study drug.
  • CCAE Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0: 2017.Available from: https_ctep_cancer_gov/protocoldevelopment/electronic_applications/docs/CTCA E_v5_Quick_R eference_5x7_pdf.) ⁇ Grade 3 hypersensitivity reaction in 2 or more subjects in a treatment group that is deemed drug related following unblinding of the study subjects o
  • the occurrence of Grade 3 eosinophilia with eosinophil-induced AEs in 2 or more subjects at any given dose level o
  • Drug-Induced Liver Injury Premarketing Clinical Evaluation. July 2009. Available from https_www_fda_gov/media/73679/download. Accessed 21 Oct 2020) of liver function parameters (confirmed by repeat sampling): o Three-fold or greater elevations above the upper limit of normal (ULN) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with elevation of serum total bilirubin to 2 ⁇ ULN, without initial findings of cholestasis (elevated serum ALP), and without another reason to explain the - 116 - NAI-1537985011v1 combination of increased aminotransferase (AT) and total bilirubin, such as viral hepatitis A, B, or C; or acute liver disease.
  • UPN alanine aminotransferase
  • AST aspartate aminotransferase
  • AT increased aminotransferase
  • total bilirubin such as viral hepatitis A, B
  • Criteria for Study Termination If the Investigator or the Sponsor become aware of conditions or events that suggest a possible hazard to patients if the clinical study continues, then the clinical study would be halted, pending full consideration of corrective measures to the protocol and/or termination. [00226] Conditions that may warrant termination of the clinical study include, but are not limited to, the following: [00227] The discovery of an unacceptable risk to the patients enrolled in the clinical study, [00228] Failure to enroll patients at the required rate; and/or [00229] A decision of the Sponsor to suspend or discontinue development of the IMP. 5.1.13.
  • End of Study Definition A participant is considered to have completed the study if he or she has completed all visits of the study including the last visit and the last scheduled procedure shown in the Schedule of Assessments, below. In some cases, end of study visit is 31 days after the last dose (1 study clinic visit). [00231] The end of the study is defined as completion of the last visit and the last scheduled procedure shown in the Schedule of Assessments in the trial globally (see below). 5.1.14. Study Assessments [00232] The Schedule of Assessments for the core study, for patients with psoriasis and for patients with atopic dermatitis, are shown in Table 6A and 6B (respectively) below.
  • the screening period (Day –42 to Day –1) includes required completion of all screening assessments (Tables 6A and 6B and Section 5.1.14.2). Vital sign assessments for eligibility can be repeated, and vital signs for eligibility may be used from any assessment performed between Day – 42 to Day – 1.
  • Patients who do not meet the criteria for participation in this trial may be rescreened once, if deemed acceptable by the Investigator after discussion with the Medical Monitor (except for troponin I levels in patients with psoriasis).
  • Baseline cardiac MRI assessments can be used for up to 6 months for re-screening patients with psoriasis. Patients should resign the ICF, re-do all procedures planned at the screening visit, and be assigned a new screening number.
  • Screening assessments are as follows: • Obtain signed informed consent - 118 - NAI-1537985011v1 • Review inclusion and exclusion criteria • For patients with psoriasis only: Cardiac MRI • Demographics • Medical and surgical history, and prior medication history. Prior medications should include general medications received within 30 days of start of screening. • Any previous therapies for psoriasis or atopic dermatitis (both topical and systemic agents, and phototherapy) should all be entered. All COVID vaccinations within the prior 3 years of the start of screening should be entered.
  • PE Physical examination
  • BMI body mass index
  • Vital signs These can be repeated for qualification for eligibility (see below, Patient Exclusion Criteria) • ECG, standard 12-lead, supine position •
  • ECG ECG
  • CRP C-reactive protein
  • Ferritin Coagulation panel (prothrombin time/international normalized ratio [PT/INR]), activated partial thromboplastin time (aPTT), and fibrinogen
  • CBC Complete blood count
  • CRP C-reactive protein
  • Ferritin Coagulation panel (prothrombin time/international normalized ratio [PT/INR]), activated partial thromboplastin time (aPTT), and fibrinogen
  • Patients are provided with a diary at the screening visit in order to complete the PP-NRS daily starting from screening and daily during the core study and at every visit during the OLE. Screening period must be a minimum of 7 days in order to collect PP- NRS between Day -7 and Day -1 and calculate a weekly average baseline score prior to Day 1.
  • Tests performed on Day 1 include the following: • Review inclusion and exclusion criteria • Weight • Medical, surgical, and prior medication history • PE including thorough skin examination • Vital signs • ECG, standard 12-lead, supine position • For patients with psoriasis only: Troponin I - 120 - NAI-1537985011v1 • CBC with differential • Chemistry panel • Immunoglobulin (IgG, IgM) • CRP • Ferritin • Coagulation panel (PT/INR, aPTT, and fibrinogen) • Urinalysis with micro
  • Double-Blind Study Treatment Period Days 3, 17, 31, and 45 procedures may include the following: • Brief physical examination (including a complete skin exam) • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Blood samples to check: - the level of XmAb27564 in the blood (Day 3 and Day 45 only) and for pharmacodynamics (to measure the response of the body to the study drug) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed.
  • Days 5, 19, 33, and 47 procedures may include the following: • Brief physical examination (including a complete skin exam) • Vital signs • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Blood samples to check: - the level of XmAb27564 in the blood (Day 5 and Day 47 only) and for pharmacodynamics (to measure the response of the body to the study drug) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed.
  • - the level of cytokines on Day 5 (soluble proteins naturally found in the blood) Days 8, 22, 36, and 50 procedures may include the following: - 122 - NAI-1537985011v1 • Brief physical examination (including a complete skin exam) • Vital signs • Electrocardiogram (ECG) • Lab tests (blood only) • Psoriasis Area and Severity Index (PASI): Measurement of the severity and extent of the psoriasis • Body Surface Area (BSA): Examination to measure the amount of the body surface that is affected by the psoriasis • Investigator Global Assessment (IGA): The study doctor assesses the severity of the disease • Dermatology Life Quality Index (DLQI): questions are asked about how the disease affects the quality of life (Day 50 only).
  • ECG Electrocardiogram
  • Psoriasis Area and Severity Index Psoriasis Area and Severity Index
  • BSA Body Surface Area
  • IGA Investigator Global Assessment
  • the study doctor assesses the severity of the
  • Days 12, 26, 40, and 54 procedures may include the following: • Brief physical examination (including a complete skin exam) • Vital signs • Lab tests (blood only) • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Additional blood samples will be taken to check: - 123 - NAI-1537985011v1 - the level of XmAb27564 in the blood (Day 12 and Day 54 only) and for pharmacodynamics (to measure the response of the body to the study drug) - the level of cytokines (soluble proteins naturally found in the blood) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed.
  • Days 15, 29, and 43 procedures may include the following: • Brief physical examination (including a complete skin exam) • Vital signs are measured 6 times; once before study drug injection and 5 times after study drug injection • Electrocardiogram (ECG) is performed 2 times: once before study drug injection and 1 time after study drug injection • Lab tests (blood and urine) • Urine pregnancy test for women of childbearing potential • COVID-19 antigen (rapid nasal swab test) • Skin biopsies and photography (Day 29 only) • Psoriasis Area and Severity Index (PASI): Measurement of the severity and extent of psoriasis • Body Surface Area (BSA): Examination to measure the amount of body surface that is affected by the psoriasis • Investigator Global Assessment (IGA): The study doctor assesses the severity of the disease • Receive study drug followed by an up to 6-hour observation period • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Additional blood samples to check: - the level of
  • a cardiac consultation and cMRI may be performed.
  • Patient remains at the study site for up to 6 hours after the study drug injection for further observation.
  • Day 57 procedures include the following: • Brief physical examination (including a complete skin exam) • Vital signs • Electrocardiogram (ECG) • Lab tests (blood and urine) • Skin biopsies and photography of total body and areas of plaque • Psoriasis Area and Severity Index (PASI): Measurement of the severity and extent of psoriasis • Body Surface Area (BSA): Examination to measure the amount of the body surface that is affected by the psoriasis • Dermatology Life Quality Index (DLQI): questions are asked about how the disease affects the quality of life.
  • BSA Body Surface Area
  • DLQI Dermatology Life Quality Index
  • IGA Investigator Global Assessment
  • the study doctor assesses the severity of disease.
  • Review of area where injection was given • Review of any medications • Review of any new or worsening medical conditions • Additional blood samples to check: - the level of XmAb27564 in the blood and for pharmacodynamics (to measure the response of the body to the study drug) ⁇ - the level of cytokines (soluble proteins naturally found in the blood) - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed.
  • IGA Investigator Global Assessment
  • the study doctor assesses the severity of disease • Review of any medications • Blood test for Myocarditis associated viruses and COVID-19 antibody. • Additional blood samples to check: - the level of XmAb27564 in the blood and for pharmacodynamics (to measure the response of the body to the study drug) - the level of cytokines (soluble proteins naturally found in the blood) - the level of anti-drug antibodies - the level of troponins (protein found naturally in the heart muscle). If the level of troponins is raised, a cardiac consultation and cMRI may be performed.
  • ADAs anti-drug antibodies
  • ADAs have the potential for neutralizing the activity or altering the PK of XmAb27564 or endogenous IL-2.
  • ADAs may also confer cytotoxic activity to cell-bound XmAb27564 or endogenous IL-2. Because IL-2 supports the development and survival of lymphocytes, lymphopenia is a potential clinical impact of ADAs.
  • ADAs have the potential for neutralizing the activity or altering the PK of XmAb ® 27564 or endogenous IL-2. ADAs may also confer cytotoxic activity to cell-bound XmAb ® 27564 or endogenous IL-2. Because IL-2 supports the development and survival of lymphocytes, lymphopenia is a potential clinical impact of ADAs.
  • lymphopenia is a potential clinical impact of ADAs.
  • Prior and Concomitant Medication For patients with atopic dermatitis the patients are to apply a stable dose of a non- prescription, non-urea containing emollient to all skin (normal skin and AD lesions) once or twice daily for ⁇ 14 days preceding the randomization visit and also are willing to maintain stable dosing of the emollient until at least the Day 57 visit. Every effort should be made to keep - 129 - NAI-1537985011v1 the same emollient throughout the study for the same body region. However, the chosen emollient may differ depending on the body region (e.g., body vs face emollient may be different).
  • Concomitant medications are defined as medications started before and continued after the first dose of XmAb ® 27564/placebo in this study.
  • All therapies (prescriptions or over-the-counter [OTC] medications, including vitamins and herbal supplements) different from the study drug is recorded in the eCRF.
  • Randomization schedules for each dose cohort are generated for patients with psoriasis and patients with atopic dermatitis separately prior to study start.
  • Each psoriasis cohort consist of 8 patients, 3 sentinel patients are randomized in a 2:1 ratio to XmAb ® 27564 or placebo and five remainder patients are randomized in a 4:1 ratio to XmAb ® 27564 or placebo.
  • 6 patients are randomized to XmAb ® 27564 and 2 patients to placebo.
  • 16 patients are randomized in a 3:1 ratio to receive XmAb ® 27564 or placebo.
  • XmAb ® 27564 or placebo is administered in a double-blind fashion.
  • the contract research organization will maintain the randomization code in a secure location with controls to prevent unauthorized access, including the computer program written to generate the randomization, randomization codes, program log, seed number used by the program, copy of the randomization plan along with approval documentation as appropriate, and the write-protected electronic storage medium.
  • the CRO will name an unblinded statistician to generate the randomization codes.
  • the pharmacists will be unblinded.
  • the site follows their internal SOP for the back-up staff who can break the blind. If possible, the Investigator notifies the Xencor Medical Monitor prior to breaking the blind, but if not, they are informed immediately thereafter. [00269] If the treatment assignment is unblinded by the Investigator, then the Investigator must notify the Sponsor in writing and document the course of events in the source records. Any patient for whom the treatment code is prematurely released will be withdrawn from the study but will continue to be followed for safety events if IMP was received. 5.1.17.
  • Study Drug and Storage is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol and the Pharmacy Manual.
  • Investigational product, dosage and mode of administration includes the following: Multiple SC administration of XmAb ® 27564 solution at dose levels of (0.007, 0.015, 0.025, 0.040, 0.065, and 0.100 mg/kg) or placebo, as shown in Table 4.
  • Table 4 Study Drug Information XmAb ® 27564 Drug Product (DP) a es gle - 132 - NAI-1537985011v1 Dose: Study drug preparations and dose administration information are provided in Example 1.
  • XmAb ® 27564 Drug Product is provided as a 30 mg vial (30 mg/mL, 1 mL fill) for SC administration. Prior to use, the XmAb ® 27564 DP vial should be visually inspected. If particulate matter and/or discoloration are noted, the drug should not be administered, and the Sponsor should be notified. Aseptic technique must be strictly observed when preparing the solution for injection since XmAb ® 27564 and XmAb ® 27564 placebo vials do not contain preservatives.
  • the XmAb ® 27564 placebo is provided as 5 mL of a solution of 250 mM sorbitol in a 20 mM histidine buffered solution of pH 6.5 in a 10 mL vial. The vial must not be shaken, as excess agitation may cause aggregate formation. Administration of XmAb ® 27564 and XmAb ® 27564 placebo should take place within 4 hours of dose preparation. If a delay is anticipated, XmAb ® 27564 and XmAb ® 27564 placebo may be stored at controlled room temperature (15oC-30oC; 59oF-86oF) for no more than 4 hours prior to injection (see the study Pharmacy Manual for specific instructions).
  • XmAb ® 27564 DP and XmAb ® 27564 placebo are administered via SC injection (1 mL syringe and 27-gauge needle).
  • Recommended sites of administration include the upper arm, thigh, and abdomen, with the regions used to be noted in the source document. Regions should be rotated from one dose to the next. The injection site should be marked with a small circle and date of injection to identify injection site and monitor reactions.
  • Dosing is weight based for all treatment groups. Calculate the dose based on the weight at the Day 1 visit. 5.1.20.
  • Psoriasis Area Severity Index (PASI) Scoring 4 main body areas are assessed: the head (h), the trunk (t), the upper extremities (u), and the lower extremities (l), corresponding to 10, 30, 20, and 40% of the total body area, respectively.
  • 3 target symptoms namely erythema (E), infiltration (I), and desquamation (D) are assessed according to a scale 0–4, where 0 means a complete lack of cutaneous involvement and 4 represents the severest possible involvement.
  • the severity rating for the 3 main target symptoms is multiplied with the numerical value of the areas involved and with the various percentages of the 4 body areas. These values are then added to obtain the PASI.
  • PASI 0.1 ⁇ Ah ⁇ (Eh + Ih + Dh) + 0.3 ⁇ At ⁇ (Et + It + Dt) + 0.2 ⁇ Au ⁇ (Eu + Iu + Du) + 0.4 ⁇ Al ⁇ (El + Il + Dl)
  • the index varies in steps of 0.1 units from 0.0 to 72.0.
  • the proportion of subjects with PASI 50, 75, and 90 represent the fraction of patients that have improvement of the PASI score of 50%, 75% and 90% over the baseline PASI (Oji and Luger. Clin Exp Rheumatol.2015;33(5 Suppl 93):S14–9.).
  • Static Investigator Global Assessment of Disease - 134 - NAI-1537985011v1 The Static Investigator Global Assessment (sIGA) of disease is a 5-point scale, without any reference to baseline (Langley et al. J Dermatolog Treat.2015;26(1):23–31.; Table 5). Table 5. sIGA of Disease for Psoriasis S core Description ; 5.1.20.3 Validated Investigator Global Assessment for Atopic Dermatitis Table 17.
  • Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD): Score Morphological Description , g - 135 - NAI-1537985011v1 [00279]
  • the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) is a static 5-point scale that was developed to assess the overall atopic dermatitis severity (Simpson et al. J Am Acad Dermatol.2020;83(3):839-846).
  • the IGA score is selected using the descriptors in Table 17 that best describe the overall appearance of the lesions at a given time point. It is not necessary that all characteristics under Morphological Description be present.
  • EASI Eczema Area and Severity Index
  • each region is assessed separately for 4 signs: erythema, edema/papulation, excoriation, and lichenification. Each sign is assigned an intensity score from 0 to 3, with 0 being absent; 1, mild; 2, moderate; and 3, severe. Half points may be used between points 1 and 3 (e.g., 1.5 and 2.5 but not 0.5) as any sign present should be treated as at least mild. It is important to note that only inflamed areas should be included in the assessment.
  • Regions that present with varying severity of a particular sign should be roughly averaged across involved areas only; half units may be useful in this scenario.
  • Region Score Each region is assigned an adult that reflects the relative contribution of that region to the total BSA. The region score is calculated separately for each region by multiplying the sum of the regional intensity score by the regional area score and the region-specific multiplier.
  • Final EASI Score The final EASI score is the summation of the 4 regional scores, ranging from 0 to 72.
  • a score of 0 indicates clear or no eczema, 0.1 to 1.0 indicates almost clear, 1.1 to 7 indicates mild disease, 7.1 to 21 indicates moderate disease, 21.1 to 50 indicates severe disease, and greater than 51 indicates very severe disease.
  • - 136 NAI-1537985011v1 5.1.20.5 Peak Pruritus Numerical Rating Scale (Atopic Dermatitis) [00285] Pruritus is assessed using the PP-NRS.
  • the PP-NRS is an 11-point scale used by patients to rate their worst itch severity over the past 24 hours with 0 indicating “No itch” and 10 indicating “Worst itch imaginable” (Yosipovitch et al., Br J Dermatol.2019;181(4):761-769).
  • Patient assessments are captured daily using a diary starting from screening until the EOS visit. Patients are provided with a diary at the screening visit and instructed to enter their pruritus scores daily.
  • the daily (24-hour) PP-NRS are recorded and the weekly mean of the daily PP- NRS are calculated. Therefore, a minimum of 7 days of screening is needed to collect PP-NRS scores between Day -7 and Day -1 and calculate a weekly average baseline score prior to Day 1.
  • Each plaque biopsied should have a photograph accompanying the biopsy. The location of the plaque(s) biopsied should be noted in the source document. 5.1.20.7 Body Surface Area of Psoriasis or Atopic Dermatitis - 137 - NAI-1537985011v1 [00288]
  • the body surface area (BSA) of psoriasis or atopic dermatitis is estimated by using the size of the handprint as 1% of the body surface area. The investigator totals the number of patient’s handprints across the patient’s body that have activity with psoriasis or atopic dermatitis (Ramsay and Lawrence. Br J Dermatol.1991;124(6):565–70.).
  • the Dermatology Life Quality Index [00289]
  • the DLQI is a short and simple quality of life (QOL) instrument that can be used in psoriasis or atopic dermatitis. It is self-administered with a mean completion time of 2 min. It consists of 10 questions concerning impact of skin diseases on different aspects of patient’s QOL over the last week.
  • the DLQI items include symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the side effects of treatment. Each item is scored on a 4-point scale: not at all/not relevant, a little, a lot and very much. Item scores (0-3) are added to give a total score (0-30); higher scores indicate greater impairment of QOL.
  • n e s s . n p e s ’ n i d t r l n e e h h e t a m o e n C d n ds t s p o e H S m r b . d o t o r o i e n o i .
  • RNA assessment The samples for RNA assessment are collected into PAXgene tubes for –70 ⁇ C freezer storage and batch shipped to the designated laboratory.
  • Treg and TBNK flow cytometry provides PD data for Treg and Teff/NK expansion and activation.
  • Isolated RNA is used for transcriptomic analysis of immune cell genes and gene signatures.
  • PBMCs is used for additional phenotypic and functional description of immune cells, including but not limited to analysis by flow cytometry or similar methods. 5.1.22.
  • AEs Adverse Events
  • Clinical laboratory safety assessments including troponin I for patients with psoriasis • ECG parameters • Vital signs • Physical exam findings • ADAs • Cardiac MRI for patients with psoriasis • Myocarditis-associated virus serology and PCR for patients with psoriasis • Pregnancy - 154 - NAI-1537985011v1 Overdose 5.1.22.1 Adverse Events [00297] An adverse event or AE is any untoward medical occurrence in a patient participating in a clinical study. The AE does not necessarily have a causal relationship with study treatment.
  • An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of an IMP.
  • AEs may include the onset of new illness and the exacerbation of preexisting conditions. AEs are classified as “serious” and “non-serious” for regulatory reporting purposes.
  • SAE Serious Adverse Event
  • Severity is a measure of intensity whereas seriousness is defined by the criteria above. For example, a mild degree of gastrointestinal bleeding requiring hospitalization for monitoring purposes would be considered an SAE but is not necessarily a severe (Grade 3) SAE. Similarly, - 155 - NAI-1537985011v1 an AE that is severe (Grade 3) is not necessarily an SAE. For example, alopecia may be assessed as severe (Grade 3) but would not be considered an SAE.
  • Adverse event monitoring begins upon the signing of the informed consent form (ICF).
  • ICF informed consent form
  • All SAEs and events of special interest, irrespective of causality, are monitored until the event has resolved or stabilized, until any abnormal laboratory values have returned to baseline or stabilized at a level acceptable to the Investigator and Sponsor’s medical representative, until there is a satisfactory explanation for the changes observed, or until the patient is lost to follow-up.
  • Adverse events may be volunteered spontaneously by the study patient, discovered by the study staff during physical examinations, or by asking an open, nonleading question such as “How have you been feeling since you were last asked by us?” or “Have you had any new or changed health problems since you were last here?” All AEs and any required remedial action are recorded.
  • the nature of AE, date (and time, if known) of AE onset, date (and time, if known) of AE outcome to date, severity, and action taken with the study drug because of - 156 - NAI-1537985011v1 the AE are documented together with the Investigator’s assessment of the seriousness on the AE and causal relationship to study drug and/or study procedure.
  • Non-serious AEs are recorded in electronic data capture (EDC) following administration of IMP through EOS, and any non-serious AEs that occur prior to dose administration are captured in the medical history. For screen failed patients recording of non-serious AEs after the ICF was signed is not needed.
  • Serious AEs or SAEs are recorded in the EDC on AE eCRF page and the completed SAE report form is emailed to Xencor/CRO vendor for all patients randomized. The Investigator is responsible, within 24 hours of becoming aware of the SAE, to complete all required details on the initial and follow-up SAE report form and email to Xencor.
  • AEs which are unlikely related or not related to study drug are considered to be not related events for the purposes of AE capture and regulatory reporting.
  • b AEs which are possibly related, probably related, or related to study drug are considered to be related events for the purposes of AE capture and regulatory reporting.
  • Xencor requests clarification of omitted and/or discrepant information from the initial notification or follow-up report(s) as needed. Xencor may also request additional information [00307] regarding the SAE in order to obtain the full clinical picture.
  • the Investigator or an authorized delegate is responsible for providing the requested information in a Data Clarification Form (DCF) to Xencor within 24 hours of the request and updating AE eCRF in EDC.
  • DCF Data Clarification Form
  • the initial SAE report from the investigational site must be followed up as soon as possible by completing a blank SAE report form (with the follow-up box checked). All additional events and existing event/s should be recorded with corresponding assessments, all new details should be included in the follow-up report.
  • These SAE report/s should be emailed along with clear photocopies of other documents as necessary (e.g., hospital reports, discharge summaries, consultant reports, autopsy reports, etc.) with the study patient’s personal identifiers redacted.
  • AE Severity/Intensity/Grades The Investigator can assess all AEs for severity, also known as intensity or grades, utilizing the NCI-CTCAE grading scale (Version 5.0). Note that some grades are not available for certain AEs (e.g., Headache can only be Grade 1, 2 or 3; and Sepsis can only be Grade 3, 4 or 5). AEs not contained within CTCAE Version 5.0 are rated on a 5-point scale (Table 9). - 158 - NAI-1537985011v1 Table 9.
  • Adverse Event Grades Mild Mild events are those which are easily tolerated with no disruption of normal daily activity. re at [00312]
  • the Investigator assess the causality/relationship between the IMP and the AE.
  • One of the following categories should be selected based on good medical and scientific judgment, considering the definitions in Table 10 and all contributing factors. Table 10.
  • Causality Assessment Guide For the purposes of regulatory reporting, if the Investigator chooses one of the following categories, “ ” e y - 159 - NAI-1537985011v1 If the Investigator chooses one of the following below, the AE is identified as “not related by the Investigator” e al ear ge. y p p g, g g .
  • the baseline laboratory test results for clinical assessment for a particular test is defined as the last measurement prior to the initial dose of study drug. • During the screening period, if a patient has an out-of-range value for a clinical laboratory parameter which the Investigator believes is not clinically significant, but the Investigator wants to confirm with a repeat laboratory test, a single repeat is allowed to confirm the initial result. If a subject tests positive for urine drugs of abuse (including the following: amphetamines/ecstasy, barbiturates, benzodiazepines, cocaine, opiates, methadone metabolites, and phencyclidine) and alcohol screens, the subject’s eligibility is discussed with the Xencor Medical Monitor.
  • urine drugs of abuse including the following: amphetamines/ecstasy, barbiturates, benzodiazepines, cocaine, opiates, methadone metabolites, and phencyclidine
  • cytokines including IL-6, IP-10, IL-23, IL-17 will be examined.
  • additional chemokines including TARC, MDC, cytokine IL-18 and Th2 biomarker periostin is examined.
  • Microscopic analysis is reflexive after urine dipstick is positive.
  • c Troponin I testing for patients with psoriasis only Serum IgE and allergen-specific. IgE for patients with atopic dermatitis only.
  • AEs Clinically significant abnormal laboratory results are recorded as AEs and the relationship to the study drug is indicated as below. Laboratory values outside the normal range assessed as clinically significant should be reported as AEs. In general, a clinically significant laboratory value or finding would require some diagnostic or therapeutic intervention other than repeating the test. 5.1.24.
  • Troponin I Cardiology Consultation, Myocarditis-associated Viruses, and Cardiac MRI
  • All patients with psoriasis have a cardiac MRI at Screening and are followed at baseline and throughout the study by serial high sensitivity Troponin I assays. Patients who have elevated Troponin I levels at screening should be screen failed.
  • a patient has a value for Troponin I above normal limits, the patient should be called back to clinic for an unscheduled visit and should have a directed physical examination, a 12-lead ECG, an urgent cardiology consultation, and a cardiac MRI.
  • Myocarditis should be diagnosed using cardiac MRI and graded by the Lake Louise criteria for myocarditis (Friedrich et al. J Am Coll Cardiol.2009 Apr 28;53(17):1475–87.; Ferreira et al. J Am Coll Cardiol.2018;72(24):3158–76.). If positive, serial cardiac MRI studies should be done until event resolution.
  • myocarditis-associated viruses should be assessed by serial titers and PCR: adenovirus, coxsackie B virus, echovirus, herpesviruses, parvovirus, and SARS-CoV-2 (Pollack et al. Nat Rev Cardiol.2015;12(11):670– 80.). - 165 - NAI-1537985011v1 [00320] Cardiac MRI data are collected and read centrally by a third party blinded to patient identity. Procedure specifics for cardiac MRI are detailed in the study manual. 5.1.25. Vital Signs [00321] Vital signs are assessed after the patient has been resting quietly for ⁇ 5 minutes and as indicated in the Schedule of Assessment (Tables 6A and 6B ).
  • vital signs should be measured prior to blood sampling.
  • the following vital signs are measured: • Blood pressure (systolic and diastolic [mmHg]) is measured after the patient has been resting quietly for at least 5 minutes. • Heart rate (beats per minute [bpm]) is collected after the patient has been resting and at rest for ⁇ 5 minutes. • Respiratory rate (breaths per minute) • Oral body temperature (°C) • Blood oxygen saturation by pulse oximetry. Oxygen saturation levels are captured at each vital sign collection. • The following vital signs abnormalities is recorded as AEs: 1. Vital signs are considered clinically significant initially and on confirmation 2. Require a patient to be discontinued from the study 3. Require a patient to receive treatment 4.
  • a complete PE (including thorough skin examination, and excluding genital, rectal, and breast examinations [unless indicated]) is performed at screening. For all other time points, - 166 - NAI-1537985011v1 symptom-directed PEs are performed; a thorough skin examination is performed at every visit. Abnormal findings is documented in the patient’s eCRF. [00325] A following abnormal PE finding that is considered clinically significant is recorded as an AE: 1. Requires the patient to be discontinued from the study, 2. Requires the patient to receive treatment; and/or 3. Requires a change or discontinuation of the study drug (if applicable) recorded as an AE. 5.1.27.
  • Electrocardiogram Assessments [00326] The timing of ECGs is noted in the Schedule of Assessment (Tables 6A and 6B). On all dosing days during the core study, supine ECGs are performed predose and 4 hours after SC injection. The 12-lead ECGs are performed after the patient has been resting supine for ⁇ 5 minutes. The ECG includes all 12 standard leads. The following ECG parameters are collected: PR interval, QRS interval, RR interval, QT interval, QTc, and QTcF interval.
  • Electrocardiogram assessments include interpretation of the tracings (e.g., rhythm, presence of arrhythmia or conduction defects, morphology, any evidence of myocardial infarction, or ST segment, T-wave, and U-wave abnormalities).
  • the Investigator or designee is responsible for reviewing and over-reading the ECG interpretation, for assessing whether the ECG machine interpretation findings are accurate, appropriate, normal or abnormal, and for providing corrected interpretations, as appropriate.
  • any abnormal ECGs are assessed for clinical significance.
  • Additional ECGs may be obtained if clinically indicated. Any additional relevant data obtained by the Investigator during the course of this study is supplied to the Sponsor.
  • ECG ECG that the Investigator considers clinically significant
  • the Investigator will: • Repeat the ECG; and/or • Follow-up ECG(s) are obtained if any significant abnormalities are detected after dose administration to document resolution and as clinically indicated.
  • Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., maternal serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, birth defect) and reported within 24 hours of awareness in accordance with the procedure for reporting SAEs.
  • Xencor-CRO vendor requests clarification of omitted or discrepant information from the initial notification. The Investigator or an authorized delegate is responsible for providing the requested information to Xencor within 24 hours of the request. 5.1.29.
  • Descriptive statistics include mean, median, standard deviation, quartiles, min and max for continuous variables, and frequency counts and percentages for categorical variables. Data is displayed graphically as appropriate.
  • PK/PD analysis of the blood include PK, ADA, transcriptomics, flow cytometry, and cytokine/soluble factor measurements as described in the following sections. [00341] After all subjects have completed the double-blind core study (subjects who did not enter extension phase had EOS visit and subjects who entered extension phase had Day 57 visit as defined in the core study assessment schedule), all the subjects’ data in the double-blind core study are locked and unblinded after the database has met the unblinding criteria as required by data management.
  • the database lock and unblinding are performed for patients with psoriasis and patients with atopic dermatitis separately. Analysis are performed on the unblinded core study data. - 169 - NAI-1537985011v1 [00342] Pharmacokinetic, ADA, and PD data are analyzed as described in the following sections. A statistical analysis plan (SAP) prespecifying details for all analyses is completed prior to database lock. Any deviations from the planned analyses is described in the final clinical study report. 5.1.30.1 Sample Size and Power [00343] No formal sample size calculations were performed. The study enrolls approximately 48 patients in total with psoriasis, with 8 patients per cohort, and approximately 80 patients with atopic dermatitis with 16 patients per cohort.
  • Analysis Set The following analysis sets are defined for the double-blind core study • Randomized Analysis Set: All patients who signed the informed consent, successfully complete screening, and receive a randomization number. • Safety Analysis Set: All patients who received any amount of XmAb ® 27564 or placebo. • Efficacy Analysis Set: All patients who received any amount of XmAb ® 27564 or placebo, have baseline and at least 1 post-baseline PASI score or EASI score for psoriasis and atopic dermatitis, respectively. • Pharmacokinetic Full Analysis Set: All patients who received a dose of XmAb ® 27564 and have at least 1 concentration data point.
  • the exploratory efficacy variables for patients with psoriasis include the following: - 170 - NAI-1537985011v1 • PASI • sIGA • BSA • DLQI
  • PASI, sIGA, BSA and DLQI The analysis of the exploratory efficacy objective of this study is based on the change from baseline to Day 57 of the efficacy variables (PASI, sIGA, BSA and DLQI).
  • PASI 75 The percentage of patients with a greater than or equal to 75% reduction from baseline in PASI score (PASI 75) is tabulated by dose cohort at each visit.
  • PASI 50 and PASI 90 are summarized in the similar manner. PASI observed values, change and percentage change from baseline values are summarized descriptively as continuous variables.
  • EASI 75 and EASI 90 are summarized in a similar manner.
  • EASI observed values, change and percent change from baseline are summarized descriptively as continuous variables.
  • the proportion of patients achieving a vIGA-AD of 0 or 1 and reduction from baseline ⁇ 2 points are summarized.
  • Observed values and change from baseline in vIGA- AD are summarized as continuous variables.
  • Observed values, change and percent change from baseline in BSA involvement and DLQI are summarized.
  • the observed values, change and percent change from baseline are summarized for weekly mean PP-NRS during the core study.
  • the weekly mean PP-NRS is calculated as the average of the reported daily PP-NRS within the week.
  • the proportion of patients achieving a reduction of ⁇ 4 points from baseline in weekly mean PP-NRS score during the core study are summarized for each week.
  • the daily PP-NRS score collected at the scheduled visits will be used in the analysis.
  • - 171 - NAI-1537985011v1 The line graphs of mean observed values, change and percent change from baseline in efficacy variables over time may be plotted.
  • the categorical response variables may be plotted in line or bar plots.
  • the SAP is provide a detailed description of analysis methods. Additional exploratory analyses may be specified in the SAP.
  • Safety variables include the following: • AEs • Physical examinations (including thorough skin examination) • Vital signs • ECG • Clinical laboratory testing: ⁇ Clinical chemistry, hematology including eosinophils, coagulation, troponin I (for patients with psoriasis only), CRP, ferritin, urinalysis, viral testing (for patients with psoriasis only), and cardiac MRI (for patients with psoriasis only) • Concomitant medications • Medical history [00353] The extent of exposure to XmAb ® 27564 or placebo is summarized by dose cohort. [00354] Summary tables and listings are provided for all reported AEs.
  • Drug names are classified by the WHO dictionary.
  • Adverse events are coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). The verbatim term recorded by the Investigator is mapped to System Organ Class (SOC) and Preferred Term using MedDRA.
  • SOC System Organ Class
  • Treatment-emergent AEs are defined as events with onset dates on or after the start of study treatment or events that are present before the first injection of XmAb ® 27654 and subsequently worsen in severity.
  • Adverse-event-related endpoints include the following: • TEAEs • Treatment-emergent SAEs (TE-SAEs) • Treatment-related TEAEs • Treatment-related TESAEs - 172 - NAI-1537985011v1 • TEAEs by severity that are defined by NCI-CTCAE, Version 5.0 [00358] All AE-related endpoints are summarized by MedDRA SOC and preferred term. At each level of summation, patient is counted once under the greatest severity and strongest study drug relationship. All AEs are included in the listings. [00359] The hematology, chemistry, and other laboratory values and change from baseline values are summarized descriptively by dose cohort.
  • the baseline value for each laboratory value is defined as the last assessment performed prior to administration of IMP.
  • Patient listings of all laboratory data collected during the study are generated. Laboratory values outside normal limits are identified in the patient listings and include flags for high and low values.
  • Vital sign results and change from baseline values are summarized descriptively for each scheduled time point.
  • the baseline value for each vital sign measurement is defined as the last assessment performed prior to administration of IMP.
  • the change in vital signs values from pre-injection are summarized for each post-injection point.
  • Pre-injection assessments are defined as last vital assessment prior to a specified injection.
  • Electrocardiogram values and change from baseline values are summarized descriptively for each scheduled time point. Patient listings of all ECG data collected during the study are generated.
  • 5.1.31. Pharmacodynamic Analyses All or key observed PD data and change from baseline data are summarized using descriptive statistics and are listed and summarized in tabular and/or graphical form. Descriptive statistics on continuous data include mean, median, standard deviation, and range, while categorical data may be summarized using frequency counts and percentages. 5.1.32. Pharmacokinetic Analysis [00363] The PK parameters are computed using noncompartmental and/or compartmental methods, whichever best describes the data. [00364] Data analysis may include assessment of dose proportionality, steady state conditions and drug accumulation with repeated dosing. [00365] In addition, population PK analysis may be conducted to develop a model to describe the concentration-time profile of XmAb ® 27564.
  • Immunogenicity is assessed by measuring serum levels of anti-XmAb ® 27564 binding antibodies by ICON Laboratory Services, Inc., using a fully validated electrochemiluminescent assay method. Immunogenicity results are listed and displayed graphically by overlaying immunogenicity parameter on drug serum concentrations over time. Incidence of confirmed positivity is summarized and additional analyses of time to onset of ADA, duration of ADA positivity, neutralizing antibodies, and impact on drug serum concentrations may also be performed. 5.1.34.
  • IL-2 Fc fusion protein e.g., XmAb ® 27564
  • XmAb ® 27564 is a monovalent interleukin-2 Fc (IL-2-Fc) fusion protein, engineered to selectively activate and expand regulatory T cells (Tregs) for the treatment of patients with autoimmune diseases.
  • IL-2-Fc monovalent interleukin-2 Fc
  • Tregs prevent autoimmunity by suppressing other immune cells from attacking normal tissue; however, in many autoimmune diseases, Tregs become dysregulated.
  • Tregs have an important role in homeostasis and in autoimmune disease (FIG.4): 1) regulatory T cells (Tregs) are CD4+FoxP3+ cells expressing CD25 (IL-2R ⁇ ) that maintain immune tolerance in tissues by suppressing the function of both CD4 and CD8 effector T cells; 2) Tregs are dysfunctional in most autoimmune diseases; 3) a therapeutic approach has been to restore Treg numbers and function via a low-dose IL-2 regimen (e.g., Treg homeostasis depends on IL-2; and IL-2 as a drug suffers from fast in vivo clearance and a narrow therapeutic index). An existing approach to restore normal immune activity and improve outcomes for patients has been to activate Tregs with IL-2 provided therapeutically at low doses.
  • IL-2 is a highly potent molecule that also activates the immune cell populations that Tregs are intended to suppress.
  • XmAb ® 27564 was engineered with reduced binding affinity for IL-2’s beta receptor (IL-2R ⁇ , CD122) and increased binding affinity for its alpha receptor (IL-2R ⁇ , CD25) to selectively target Tregs, and with 400- to 1000-fold reduced potency to improve the half-life of XmAb ® 27564 and to reduce its toxicity compared to wildtype IL-2 (FIG.5).
  • XmAb ® 27564 is based on XmAb ® cytokines approach for creating cytokine therapies (e.g., overcomes native - 180 - NAI-1537985011v1 cytokine short half-life and high toxicity; and systematically engineer a broad portfolio of cytokines). Integration of XmAb ® heterodimeric Fc domain provides a stable protein scaffold and improves XmAb ® 27564 pharmacologic properties. The XtendTM technology enhanced XmAb ® 27564 circulating half-life. In preclinical studies, XmAb ® 27564 was well-tolerated, promoted the selective and sustained expansion of Tregs and exhibited a favorable pharmacokinetic profile.
  • XmAb® 27564 exhibited extended half-life and good tolerability in non-human primates (NHPs); and XmAb®27564 selectively promoted Tregs and extended half-life due to low potency and XtendTM Fc domain (FIGS.6A-6B).
  • Approximately 1000X reduction in binding of XmAb ® 27564 to IL2-R ⁇ resulted in reduced overall potency and greater selectivity for Treg activation over conventional T cells (Tcons) and natural killer (NK) cells (FIGS.6A-6B; Treg EC50 of 21nM and 0.06nM, respectively).
  • XmAb ® 306 The loss of internalization in vivo through IL-2R ⁇ resulted in large gains in pharmacological exposure (FIGS.6C-6D). It has been shown that second potency-tuned XmAb Cytokine program (e.g., XmAb ® 306) showed marked target cell expansion and good tolerability in human clinical trials. XmAb ® 306, an IL15-IL15R ⁇ -Fc fusion in oncology, showed consistent and robust dose-dependent NK cell expansion and accumulation upon repeat dosing, reaching 40-100x higher than baseline in higher dose cohorts.
  • the Phase 1a studies using XmAb ® 27564 showed that XmAb ® 27564’s design gave dramatic Treg increases and unprecedented durability for a single dose, with high levels of Treg populations sustained for at least 3 weeks.
  • the Phase 1a study enrolled 48 healthy subjects, with six dose-level cohorts each randomizing six subjects to an IL-2 Fc fusion protein (e.g., XmAb ® 27564) and two subjects to placebo.
  • a dose escalation review committee reviewed each cohort’s safety, immunogenicity, PK, and PD data before approving each dose escalation.
  • Each subject was admitted to the study unit for a total of 4 overnight stays; subjects returned for outpatient assessments through 21 days and were followed for safety an additional 30 days. After Cohort 3, the safety follow-up period was extended from 30 days to 45 days.
  • a total of 12 subjects received placebo (2 subjects for each of the six dose-level cohorts).
  • the demographics of the subjects in this study is provided in Table 15. Assessments were determined at Days -1, 0, 8, 10, 21, and 43.
  • the outcome measures were: - 181 - NAI-1537985011v1 1) safety and tolerability; and 2) pharmacokinetics in healthy subjects including analysis of immunomodulatory biomarkers (e.g., T-cell populations).
  • immunomodulatory biomarkers e.g., T-cell populations.
  • the most common adverse event was injection site reaction observed in 25 of 36 subjects (69%) of subjects receiving XmAb ® 27564, including: 4 of 6 (67%) receiving 0.003 mg/kg (Cohort 1); 2 of 6 (33%) receiving 0.007 mg/kg (Cohort 2); 3 of 6 (50%) receiving 0.015 mg/kg (Cohort 3); 5 receiving 0.025 mg/kg and 5 receiving 0.040 mg/kg (Cohorts 4 and 5, respectively), and in all subjects (100%) receiving 0.065 mg/kg XmAb ® 27564 (Cohort 6). All AEs of injection site reaction were mild in severity for Cohorts 1 through 3.
  • the dose-dependent PK profile is in line with the expected PD effect of XmAb ® 27564 represented by an increase in target receptor levels (CD25) on T-cells and the consequent impact of target mediated drug disposition on XmAb ® 27564 elimination.
  • One subject was confirmed positive for anti-drug antibody (ADA) at a low magnitude on day 45 postdose with no apparent impact on the PK or PD profile of XmAb ® 27564.
  • ADA anti-drug antibody
  • Treg expansion Further increases in Treg expansion were seen at dose levels higher than 0.015 mg/kg with the clearest increase observed at the highest 0.065 mg/kg dose level.
  • total Tregs increased to a peak mean 7.34-fold increase corresponding to a mean increase of 187 ⁇ 183 cells/microliter on Day 15 (FIGS.17A-17F).
  • the majority of these Tregs were CD25 hi Tregs, which were present at very low levels at baseline (mean of 2 ⁇ 1 cells/microliter) and were 117-fold induced to a maximum mean of 140 ⁇ 78 cells/microliter.
  • CD25hi Tregs are thought to be functionally highly immunosuppressive Tregs.
  • the expanded Tregs were characterized and the population was identified as activated/memory Treg (CD45RA-/FoxP3 high ) (FIGS.18A-18H), which is also positive for various immunoregulatory molecules including LAG3 (CD223), ICOS (CD278), TIGIT, 4-1BB (CD137), Fas (CD95), are HLA-DR high and Ki67 positive, consistent with a highly activated, proliferative, and immunosuppressive phenotype.
  • IL-10 an immunosuppressive cytokine produced by Tregs
  • serum levels of IL-10 were increased in a dose- dependent manner, and at the highest dose level of 0.065 mg/kg were 15-fold increased at Day 10 after treatment, and a peak mean 16-fold increase in serum IL-10/IFN-g ratio occurred at Day 15 (FIGS.19A-19B).
  • XmAb ® 27564 selectively induced Tregs that co-expressed - 183 - NAI-1537985011v1 high levels of FoxP3, CD25 as well as LAG3/4-1BB/ICOS/TIGIT and peripheral elevations in IL-10, consistent with systemic immunosuppressive bioactivity.
  • Treg expansion was not paralleled by a concomitant increase in effector lymphocyte expansion. Consistent with the intended Treg selectivity of XmAb27564, conventional or all non-Treg cells (Tcons) and NK cells were minimally increased at doses higher than 0.015 mg/kg ( ⁇ 2-fold increases).
  • Tecons non-Treg cells
  • NK cells were minimally increased at doses higher than 0.015 mg/kg ( ⁇ 2-fold increases).
  • Eosinophilia is also an expected class effect of low-dose IL-2 and engineered IL-2, likely secondary to production of the eosinophil recruitment factor IL-5 by CD25-positive ILC2 cells. IL-5 increased in a dose-responsive manner and was paralleled by asymptomatic eosinophilia (FIGS.20 and 21).
  • XmAb27564 by two design features: namely reduction of clearance as a consequence of reduced CD122/CD132 engagement and inclusion of the Fc-Xtend domain, enabling augmented duration of PK and PD activity. Indeed, subcutaneous XmAb27564 exhibited a prolonged terminal half-life of 9 to 11 days. Peak Treg expansion of 7.34-fold was seen at Day 15, and the expansion was durable with Treg expansion present at least 21 days after a single dose, boding well for MAD dosing at Q2W or longer. Table 15.
  • Terminal half-life is estimated to be 9-10 days at lower doses and 6-7 days at the highest dose, consistent with an increase in CD25 target-mediated clearance on the expanding Treg population.
  • the Phase 1a study showed that XmAb ® 27564 promoted robust and durable expansion of CD25 bright Tregs (FIGS.8A-8B).
  • the study demonstrated that a single dose of an - 185 - NAI-1537985011v1 IL-2 Fc fusion protein (e.g., XmAb ® 27564) was well tolerated and generated a durable, dose- dependent and selective expansion of Tregs (FIG.8A).
  • Tregs CD25 bright regulatory T cells
  • XmAb ® 27564 was well tolerated including at the highest dose evaluated (0.065 mg/kg).
  • a 117-fold mean peak expansion over baseline in CD25 bright cells was observed, with an 8-fold expansion in the bulk/total Treg population (FIG.8B and FIG.10B, respectively).
  • Treg baseline counts are low integer values, leading to variability in fold change calculations.
  • FIGS.8A-8B are the mean values. Peak fold change is the peak CD25 bright FoxP3 + CD4 Treg cell absolute count at a post-treatment time point divided by absolute count at baseline (NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test) [00383]
  • the Phase 1a study showed that XmAb ® 27564 promoted robust and durable expansion of CD25 bright Treg/Tcon ratio (FIGS.9A-9B). The ratio of Tregs to conventional T cells also increased significantly in a dose-dependent manner (FIGS.9A-9B). Treg baseline counts are not used in Treg/Tcon ratio calculations, leading to less variability in ratio values.
  • FIGS.9A-9B are the mean values. Dashed horizontal middle line represents the average of pre-dose values from all 48 subjects with ⁇ 2SD shown in grey lines above and below the middle dashed line (NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test). [00384] XmAb ® 27564 promoted robust and durable expansion of total Tregs (FIGS.10A- 10B). The numeric value in FIGS.10A-10C are the mean values.
  • the peak fold change is the peak CD25 + FoxP3 + CD4 Treg cell absolute count at a post-treatment time point divided by absolute count at baseline (NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test).
  • FIG.10A shows that at the highest dose level of 0.065 mg/kg, the peak total Tregs increased by 8.31-fold, corresponding to a mean increase of 193 ⁇ 122 cells/microliter on Day 15. The majority of these Tregs were CD25 bright Tregs (FIG.
  • CD25 bright Tregs are believed to be functionally highly immunosuppressive Tregs.
  • - 186 - NAI-1537985011v1 At day 21, both CD25 bright and total Treg counts remained markedly elevated, potentially supporting a multi-week dosing profile (FIGS.11A-11B).
  • the numeric values in FIGS.11A-11B are the mean values (NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test).
  • FIGS.12A-12C show that such increases are within normal ranges or within 2 SD of baseline. Dashed horizontal middle line in FIGS.12A-12C represent the average of pre-dose values from all 48 subjects with ⁇ 2SD shown in grey lines above and below the middle horizontal dashed line.
  • CD56 bright NK cells a potentially immunosuppressive cell type, were increased in a dose-dependent manner, as reported with other biologics in the class (FIG.12D).
  • Peak fold induction of CD25 bright and total Treg cells showed consistent dose response of Treg populations to XmAb ® 27564 (FIGS.13A-13B).
  • the numeric value in FIGS.13A-13B is the mean values (NS: p>0.05, *: p ⁇ 0.05, **: p ⁇ 0.01, ***:p ⁇ 0.001 compared with placebo treated cohort, Wilcoxon test).
  • the ratio of CD25 bright /Tcon and total Treg/Tcon peak fold induction showed consistent dose response of Treg populations to XmAb ® 27564 (FIGS.14A-14B).
  • the numeric value in FIGS.14A-14B is the mean value.
  • Pharmacokinetics (PK) The pharmacokinetics studies showed that the terminal half- life of about 9 to 11 days was observed across doses ranging from 0.003 mg/kg to 0.065 mg/kg of XmAb ® 27564 (FIG.15).
  • NK cells natural killer cells
  • Tcons conventional T cells
  • XmAb ® 27564 was well tolerated and generated a durable, dose-dependent and selective expansion of Tregs with a single dose. For example, 117-fold mean peak expansion over baseline in CD25 bright cells and 8-fold mean peak expansion in total Tregs at highest dose was observed; marked elevation of Tregs sustained through at least day 21: CD25 bright and total Tregs increased 44-fold and 4.5-fold at highest dose, respectively; Treg/Tcon ratio increased significantly in a dose-dependent manner; and all AEs Grade 1/2 resolved without intervention.
  • XmAb ® 27564 is a potency-tuned, monomeric human IL-2 heterodimeric Fc-fusion protein with extended half-life and increased binding affinity for IL-2 receptor alpha (CD25) designed o selectively expand regulatory T cells (Tregs).
  • XmAb ® 27564 - 188 - NAI-1537985011v1 selectively induced Tregs and was well tolerated.
  • XmAb ® 27564 PK and PD may support extended multi-week dosing intervals and has a Treg induction magnitude and durability that may be competitive or superior to other engineered IL-2 candidates in clinic.
  • the first patient has been dosed in a newly initiated Phase 1b, multiple-ascending dose study of XmAb ® 27564 in patients with atopic dermatitis and psoriasis. Multiple dosing schedules are to be explored based on pharmacodynamics data (e.g., initially at every two weeks (Q2W) for lowest doses). * * * * * * * [00394] It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Selon certains aspects, l'invention concerne des méthodes de traitement du psoriasis en plaque ou de la dermatite atopique comprenant l'administration d'une protéine de fusion Fc d'interleukine-2 (IL-2).
PCT/US2023/073577 2022-09-07 2023-09-06 Protéine de fusion fc d'il-2 destinée à être utilisée dans des méthodes pour le traitement du psoriasis en plaque et de la dermatite atopique WO2024054868A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202263404476P 2022-09-07 2022-09-07
US63/404,476 2022-09-07
US202263423467P 2022-11-07 2022-11-07
US63/423,467 2022-11-07
US202363504925P 2023-05-30 2023-05-30
US63/504,925 2023-05-30

Publications (1)

Publication Number Publication Date
WO2024054868A1 true WO2024054868A1 (fr) 2024-03-14

Family

ID=88413922

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/073577 WO2024054868A1 (fr) 2022-09-07 2023-09-06 Protéine de fusion fc d'il-2 destinée à être utilisée dans des méthodes pour le traitement du psoriasis en plaque et de la dermatite atopique

Country Status (1)

Country Link
WO (1) WO2024054868A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017127514A1 (fr) * 2016-01-20 2017-07-27 Delinia, Inc. Molécules activant sélectivement des lymphocytes t régulateurs pour le traitement de maladies auto-immunes
WO2019125732A1 (fr) * 2017-12-19 2019-06-27 Xencor, Inc. Protéines de fusion il-2 fc modifiées
US20210308222A1 (en) * 2016-11-08 2021-10-07 Delinia, Inc. Il-2 variants for the treatment of autoimmune diseases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017127514A1 (fr) * 2016-01-20 2017-07-27 Delinia, Inc. Molécules activant sélectivement des lymphocytes t régulateurs pour le traitement de maladies auto-immunes
US20210308222A1 (en) * 2016-11-08 2021-10-07 Delinia, Inc. Il-2 variants for the treatment of autoimmune diseases
WO2019125732A1 (fr) * 2017-12-19 2019-06-27 Xencor, Inc. Protéines de fusion il-2 fc modifiées

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JAMES A WELLS ET AL: "Attacking Cancer Cell Surfaceomes with Recombinant Antibodies Bispecific, Soluble TCR as the Next Therapeutic Platform 18-22 NOVEMBER 2019 ? LISBON, PORTUGAL ? LISBON CONGRESS CENTER Training Seminars n Deep Sequencing and Single Cell Analysis n Intro to Bispecifics n Genome Editing with CRISPR n Bi", 20 June 2019 (2019-06-20), XP055599264, Retrieved from the Internet <URL:https://www.pegsummiteurope.com/docs/librariesprovider8/agendaaa/pegs-europe-2019-brochure.pdf> [retrieved on 20190625] *

Similar Documents

Publication Publication Date Title
Cavelti-Weder et al. Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes
JP5905534B2 (ja) 多発性硬化症を治療する方法
US11795216B2 (en) Antibodies neutralizing GM-CSF for use in the treatment of rheumatoid arthritis or as analgesics
WO2021202563A1 (fr) Méthodes de traitement d&#39;une infection à coronavirus
Parnes et al. Pharmacokinetics, safety, and tolerability of tezepelumab (AMG 157) in healthy and atopic dermatitis adult subjects
JP2010132660A5 (fr)
Hollins et al. Long-standing dermatitis treated with dupilumab with subsequent progression to cutaneous T-cell lymphoma
JP2021100956A (ja) インターロイキン１７（ｉｌ−１７）アンタゴニストを用いてｘ線陰性体軸性脊椎関節炎を治療する方法
US20210196822A1 (en) Treatment of triple negative breast cancer with targeted tgf-b inhibition
JP2023513833A (ja) ヒト抗ｔｓｌｐ抗体の製剤及びそれを使用する方法
KR20240004451A (ko) Ilt7 결합 단백질을 이용한 자가면역 장애의 치료 방법
US20230074793A1 (en) Treatment with a bispecific antibody that binds ctla4 and pd1
Shear Fulfilling an unmet need in psoriasis: do biologicals hold the key to improved tolerability?
JP2006511620A (ja) 抗ｃｄ３抗体による潰瘍性大腸炎の処置方法
WO2024054868A1 (fr) Protéine de fusion fc d&#39;il-2 destinée à être utilisée dans des méthodes pour le traitement du psoriasis en plaque et de la dermatite atopique
Applebee et al. early stage and long term treatment of multiple sclerosis with interferon-β
US20230340110A1 (en) Dosages
WO2024126431A1 (fr) Agents de liaison anti-ilt7 pour le traitement et la prévention de la myosite
Riese SIGNATURE PAGE (SPONSOR)
Gay et al. Safety and Immunotherapeutic Activity of an Anti-PD-1 Antibody (Cemiplimab) in HIV-1-infected Participants on Suppressive cART: A Phase I/II, Double-blind, Placebo-controlled, Ascending Multiple Dose Study
Chou PROTOCOL NO.: ARU-1801_Ph1_01
CN117203232A (zh) 用抗il-13抗体治疗特应性皮炎的方法
WO2023056305A1 (fr) Échafaudages dérivés de tn3 spécifiques à cd40l destinés à être utilisés dans le traitement et la prévention de la polyarthrite rhumatoïde
CN118076369A (zh) Cd40l特异性tn3衍生支架及其用于治疗和预防类风湿性关节炎的方法
Saltz et al. Phase IIStudy to Assess the Efficacy of Durvalumab (MEDl4736) and Tremelimumab Plus Radiotherapy or Ablation in Patients with Metastatic Colorectal Cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23790166

Country of ref document: EP

Kind code of ref document: A1