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US-12622911-B2 - Methods and compositions for the treatment of pulmonary fibrosis using volasertib

US12622911B2US 12622911 B2US12622911 B2US 12622911B2US-12622911-B2

Abstract

Disclosed herein are methods for treating an individual having, or at risk of having, pulmonary fibrosis, wherein volasertib, a salt thereof, or hydrate thereof, is administered to the individual in need thereof. In one aspect, the pulmonary fibrosis may be idiopathic pulmonary fibrosis. The volasertib may be administered in an amount and for a duration of time effective to achieve one or more outcomes selected from decreased invasiveness of pulmonary fibroblasts, increased clearance of myofibroblasts, decreased migration of pulmonary fibroblasts, decreased pulmonary fibroblast proliferation, decreased cell adhesion of pulmonary fibroblasts, decreased myofibroblast activation, decreased extracellular matrix (ECM) accumulation or production, and improved lung function.

Inventors

  • Satish Kumar MADALA

Assignees

  • CHILDREN'S HOSPITAL MEDICAL CENTER

Dates

Publication Date
20260512
Application Date
20221025

Claims (17)

  1. 1 . A method for treating an individual for idiopathic pulmonary fibrosis comprising administering volasertib, or a salt thereof, or hydrate thereof.
  2. 2 . The method of claim 1 wherein said administering is in an amount and for a duration of time effective to attenuate fibrosis progression associated with pulmonary fibrosis.
  3. 3 . The method of claim 1 wherein said administering is in an amount and for a duration of time effective to achieve one or more outcomes selected from decreased invasiveness of pulmonary fibroblasts, increased clearance of myofibroblasts, decreased migration of pulmonary fibroblasts, decreased pulmonary fibroblast proliferation, decreased cell adhesion of pulmonary fibroblasts, decreased myofibroblast activation, decreased extracellular matrix (ECM) accumulation or production, and improved lung function.
  4. 4 . The method of claim 1 wherein said administering is in an amount and for a duration of time effective to improve lung function, wherein lung function is measured by one or more of spirometry, pulse oximetry, exercise stress test or arterial blood gas test.
  5. 5 . The method of claim 1 , further comprising administering a second agent selected from one or more of nintedanib, pirfenidone, tocilizumab, nivolumab, pembrolizumab, pidilizumab, lambrolizumab, atezolizumab, durvalumab, avelumab, ofnivolumab, and ipilmumab.
  6. 6 . The method of claim 5 , wherein said second agent is administered prior to said volasertib administration.
  7. 7 . The method of claim 1 , wherein said administration comprises a loading dose and a maintenance dose.
  8. 8 . The method of claim 1 , wherein said administration comprises a loading dose and a maintenance dose, wherein said loading dose is larger than said maintenance dose.
  9. 9 . The method of claim 1 , wherein said individual is an adult.
  10. 10 . The method of claim 1 , wherein said individual is under 18 years of age.
  11. 11 . The method of claim 1 , wherein said individual is pre-pubescent.
  12. 12 . The method of claim 1 , wherein said administration is selected from one or more of oral, parenteral, intravenous, and subcutaneous.
  13. 13 . The method of claim 1 , wherein said administration is via inhalation.
  14. 14 . The method of claim 1 , wherein said volasertib is administered at an interval selected from twice a day, three times a day, daily, every other day, every three days, every four days, every five days, every six days, weekly, every two weeks, every three weeks, and monthly.
  15. 15 . The method of claim 5 , wherein said second agent is administered simultaneously with said volasertib administration.
  16. 16 . The method of claim 5 , wherein said second agent is administered after said volasertib administration.
  17. 17 . The method of claim 1 , wherein the administering comprises administering to the individual from 90 mg to 500 mg of volasertib, or a salt thereof, or hydrate thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Application Ser. No. 63/272,256, filed Oct. 27, 2021, entitled “Therapeutic Inhibition of the WT1-MYCN-PLK1 Axis and Pulmonary Fibrosis Using Volasertib,” the contents of which is incorporated in its entirety for all purposes. STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH This invention was made with government support under W81XWH-17-1-0666 awarded by the Defense Advanced Research Projects Agency, and HL134801 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Pulmonary fibrosis is the final common pathway of several aging-associated chronic lung diseases that are associated with excessive fibroproliferation, survival, and deposition of the extracellular matrix (ECM) in the lung parenchyma. With aging, fibrosis occurs in both idiopathic pneumonia and systemic connective-tissue diseases. Idiopathic Pulmonary Fibrosis (IPF) is perhaps the most pernicious and enigmatic form of lung fibrosis and recent evidence indicates that the prevalence of this disease is increasing in the U.S. and around the world. The advent of two FDA-approved therapies for IPF has energized the field, but enthusiasm is tempered by the recognition that their side effect profiles are formidable and their effects are suppressive rather than remission-inducing or curative. New and better drugs for treatment of pulmonary fibrosis are needed. BRIEF SUMMARY Disclosed herein are methods for treating an individual having, or at risk of having, pulmonary fibrosis, wherein volasertib, a salt thereof, or hydrate thereof, is administered to the individual in need thereof. In one aspect, the pulmonary fibrosis may be idiopathic pulmonary fibrosis. The volasertib may be administered in an amount and for a duration of time effective to achieve one or more outcomes selected from decreased invasiveness of pulmonary fibroblasts, increased clearance of myofibroblasts, decreased migration of pulmonary fibroblasts, decreased pulmonary fibroblast proliferation, decreased cell adhesion of pulmonary fibroblasts, decreased myofibroblast activation, decreased extracellular matrix (ECM) accumulation or production, and improved lung function. BRIEF DESCRIPTION OF THE DRAWINGS Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way. FIG. 1. Volasertib therapy inhibits the WT1-MYCN-PLK1 axis to attenuate fibroblast activation including fibroproliferation, survival, and ECM production. FIG. 2. The loss of WT1 attenuates pulmonary fibrosis. All four groups of mice were treated with Dox for 4 weeks. (1) WT1 transcripts quantified in the total lung using RT-PCR (B) Total right lung collagen quantified using hydroxyproline assay (N=4-5/group; *P<0.05, **P<0.005, ***P<0.0005. FIG. 3. Overexpression of WT1 in fibroblasts augments bleomycin-induced pulmonary fibrosis. Mice were treated with tamoxifen (twice/week) and bleomycin (day 0 and 21) for total 5 wks. (A) Transcripts of WT1, MYCN, PLK1, Col1α, Col3α, Col5α and FN1 were quantified in the total lung using RT-PCR. (B) Representative Masson's Trichrome staining for lung collagen is shown in blue. Scale bar, 1500 μm. (C) Quantification of collagen staining in lung sections of PDGFRαCreER (Control) and PDGFRαCreERWT1OE (WT1OE) mice treated with bleomycin and tamoxifen (N=3/group; *P<0.05). FIG. 4. Comparative analysis of WT1 target genes identified using ChIP-seq that either up- or down-regulated in IPF lungs. FIG. 5. WT1 is positive regulator of anti-apoptotic gene expression. (A) The loss of WT1 attenuated anti-apoptotic gene transcript levels including BCL3, BCL2XL, and BCL2L2 in IPF fibroblasts. (B) Overexpression of WT1 induces pro-apoptotic gene transcript levels including BCL3, BCL2XL, and BCL2L2 in normal fibroblasts. *P<0.05. FIG. 6. WT1 is a positive regulator of fibroblast survival. IPF fibroblasts were treated with control or WT1-specific siRNA for 48 hours, and FasL-induced apoptosis was analyzed. ****P<0.00005. FIG. 7. MYCN expression during lung development. MYCN transcripts decrease in the postnatal period of lung development. ****p<0.00005. FIG. 8. Upregulation of MYCN in IPF Lungs. MYCN transcript levels are increased in total transcripts of IPF lungs compared to normal lungs. *p<0.05. FIG. 9. MYCN-positive fibroblasts accumulate in the distal areas of IPF Lungs. Top Panels: Normal lung shown at low (Scale bar, 500 μm) and high magnification (Scale bar, 50 ρm). Bottom Panels: Spindle-shaped nuclei of MYCN-positive fibroblasts indicated using arrows in high magnification images of subpleura and fibrotic foci of IPF lung. Scale Bar, 50 μm. FIG. 10. WT1 is a positive regulator of MYCN expression. The knockdown of WT1 attenuates MYCN expression in lung resident fibroblasts isolated from IPF lungs (N=3;