WO2024059336A1 - Inhibition de la voie du récepteur 2 activé par la protéase (par2) pour le traitement et la prévention du lymphoedème - Google Patents

Inhibition de la voie du récepteur 2 activé par la protéase (par2) pour le traitement et la prévention du lymphoedème Download PDF

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WO2024059336A1
WO2024059336A1 PCT/US2023/033043 US2023033043W WO2024059336A1 WO 2024059336 A1 WO2024059336 A1 WO 2024059336A1 US 2023033043 W US2023033043 W US 2023033043W WO 2024059336 A1 WO2024059336 A1 WO 2024059336A1
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lymphedema
composition
par2
inhibitor
tslp
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PCT/US2023/033043
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Babak J. MEHRARA
Hyeung Ju PARK
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Memorial Sloan Kettering Cancer Center
Sloan-Kettering Institute For Cancer Research
Memorial Hospital For Cancer And Allied Diseases
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Publication of WO2024059336A1 publication Critical patent/WO2024059336A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C07K16/245—IL-1
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0625—Epidermal cells, skin cells; Cells of the oral mucosa
    • C12N5/0629—Keratinocytes; Whole skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • lymphedema It is estimated that 25-40% of patients who undergo surgical treatment for solid tumors develop lymphedema. 5 [0005] Several lines of evidence suggest that the pathophysiology of lymphedema is related to chronic cutaneous T-helper cell inflammatory responses. 18,22,23,25,28-36 CD4 + T cell abundance is increased in clinical biopsy specimens, and this inflammatory response positively correlates with severity of disease. 17 Depletion of CD4 + T cells (but not CD8 + PATENT MSKCC.056.WO1 cells, natural killer cells, macrophages, or B cells) in mouse models prevents the development of lymphedema and effectively treats established disease.
  • Keratinocytes are skin cells that that make up 90% of the epidermis and originate as stem cells in basal layers of the skin. Keratinocytes proliferate, differentiate, and migrate to the more superficial layers of the skin ultimately forming the cornified layer. Major functions of keratinocytes include maintenance of skin barrier function, prevention of water loss, and inhibition of bacterial infiltration. 71 Proliferation and differentiation of keratinocytes is controlled by diverse cytokines such as Interleukin (IL) 1 ⁇ , IL1 ⁇ , epithelial growth factor (EGF), transforming growth factor 1 ⁇ (TGF1 ⁇ ) and tumor necrosis factor ⁇ (TNF ⁇ ).
  • IL Interleukin
  • IL1 ⁇ epithelial growth factor
  • TGF1 ⁇ transforming growth factor 1 ⁇
  • TGF ⁇ tumor necrosis factor ⁇
  • Keratins are a large family of intermediate filaments that are expressed by keratinocytes and are necessary for maintenance of cytoskeletal integrity and cellular motility.
  • 61 KRT14-KRT5 are expressed by keratinocytes and keratinocyte precursors in the stratum basale. As the cells migrate suprabasally and become differentiated, expression of KRT14-KRT5 heterodimers is replaced by KRT10-KRT1.
  • KRT16, KRT17, and KRT6 are expressed in activated, PATENT MSKCC.056.WO1 proliferating keratinocytes in pathological or physiological conditions such as atopic dermatitis, psoriasis, wound healing, and burns.
  • Epidermal changes are a prominent finding in lymphedema and include hyperkeratosis, acanthosis, spongiosis, and parakeratosis with elongated rete edges. 42,43 These skin changes are similar to the epidermal changes in atopic dermatitis (AD). 44 As with lymphedema, the pathology of AD is also regulated by Th2 inflammatory responses—importantly, epidermal changes in AD are a primary event and precede infiltration of Th2 cells in the skin. Keratinocytes regulate Th2 inflammatory responses and development of AD by producing Th2-inducing cytokines, such as thymic stromal lymphopoietin (TSLP), IL33, and IL25.
  • TSLP thymic stromal lymphopoietin
  • cytokines act on na ⁇ ve CD4 + cells through dendritic cells (DCs) to prime Th2 differentiation, regulate cytokine and migratory responses of antigen-presenting cells, and stimulate proliferation of granulocytes that release Th2 cytokines.
  • DCs dendritic cells
  • Th2 response in AD is highlighted by the efficacy of dupilumab, a monoclonal antibody that prevents IL4/IL13 signaling. 55
  • the parallels between AD and lymphedema suggest that keratinocytes may play an important role in the pathophysiology of secondary lymphedema.
  • keratinocytes are known to play a key role in the pathophysiology of psoriasis and AD, no prior studies have tested whether these cells also contribute to the pathology of secondary lymphedema.
  • pharmacologic therapies available for the treatment of lymphedema.
  • Current treatments for secondary lymphedema decongestive therapy, compression garments, external pumps, and surgery—are inadequate and costly.
  • 6-13 surgical treatments designed to bypass lymphatic channels or promote development of collateral lymphatics are helpful in some patients; however, these procedures are not effective for patients with advanced disease and can cause additional morbidity. 14-16 Accordingly, there is a need in the art for novel treatments for lymphedema.
  • a sensor for proteolytic enzymes that regulates the expression of Th2-inducing cytokines by keratinocytes in AD, 56,57 and Th2-inducing cytokines by keratinocytes in lymphedema Furthermore, we show that proliferation and activation of keratinocytes are induced by exposure to lymphatic fluid, and that inhibition of PAR2 activation or PAR2-expression cell proliferation attenuates the expression of Th2-inducing cytokines.
  • the invention provides a method of treating or preventing lymphedema, the method comprising administering to a subject having lymphedema or susceptible to developing lymphedema a composition comprising an effective amount of a PAR2 inhibitor or an inhibitor of a Th2-inducing cytokine.
  • the invention provides a pharmaceutical composition comprising a PAR2 inhibitor or an inhibitor of a Th2-inducing cytokine for use in a method of treating or preventing lymphedema.
  • the Th2- inducing cytokine is selected from the group consisting of TSLP, IL33, and IL25.
  • the composition comprises a PAR2 inhibitor.
  • the PAR2 inhibitor is selected from the group consisting of a peptide, a peptidomimetic, a pepducin, a small-molecule compound, and an anti-PAR2 antibody or antigen binding fragment thereof.
  • the PAR2 inhibitor is ENMD-1068.
  • the composition comprises a TSLP inhibitor.
  • the TSLP inhibitor is a small-molecule compound or anti-TSLP antibody or antigen-binding fragment thereof.
  • the TSLP inhibitor is selected from the group consisting of Baicalein, Tezepelumab, or Ecleralimab.
  • the composition does not comprise teriflunomide.
  • the composition is administered topically or subcutaneously.
  • the subject of the treatment is a human subject.
  • PATENT MSKCC.056.WO1 Lymphedema can arise from multiple causes, including abnormal development of the subject’s lymphatic system or lymphatic injury.
  • the lymphedema can be congenital.
  • the lymphatic injury can result from surgery, trauma, radiation, chemotherapy, fibrosis of lymph tissue, infection (including viral, bacterial, and/or parasitic infection), or burns.
  • the lymphatic injury can result from removal, ligation, or obstruction of lymph nodes or lymph vessels.
  • the lymphatic injury can result from joint replacement surgery.
  • the composition comprising the PAR2 inhibitor or inhibitor of a Th2-inducing cytokine is administered prophylactically within about six weeks, preferably within about two weeks, of the lymphatic injury.
  • the subject has undergone or is undergoing treatment for cancer.
  • the treatment with the PAR2 inhibitor or inhibitor of a Th2-inducing cytokine can commence before or concurrently with the cancer treatment.
  • Cancer treatments can include surgery, chemotherapy, and radiation.
  • the cancer comprises a solid tumor.
  • the subject is obese, overweight, or diabetic and has lymphatic dysfunction, swelling, or lymphedema from these conditions.
  • the methods and compositions of the invention are preferably used to treat or prevent chronic lymphedema.
  • the invention also provides a method for inhibiting activation of keratinocytes, the method comprising exposing keratinocytes to an effective amount of a PAR2 inhibitor or an inhibitor of a T-helper 2 (Th2)-inducing cytokine.
  • the method is an in vitro method.
  • Fig.1A-1H show that lymphedema results in hyperkeratosis and expression of Th2-inducing cytokines.
  • Fig.1A shows demographics of patients with unilateral BCRL who provided samples for our study. Data are mean ⁇ standard deviation unless noted.
  • Fig.1C shows representative images of H&E and immunofluorescent staining of Ki67, KRT6, and KRT14 in normal and lymphedematous (LE) skin biopsies from patients with unilateral BCRL.
  • FIG. 1D shows quantification of epidermal area, Ki67 + cells, and KRT6 and KRT14 area in normal and lymphedematous (LE) skin biopsies from patients with unilateral BCRL.
  • HPF high-power field
  • Fig.1F shows representative immunofluorescent images of KLK5, PAR2, TSLP, and IL33 staining in normal and lymphedematous (LE) skin biopsies from patients with unilateral BCRL. Dashed lines indicate the thickness of epidermis. Scale bar: 50 ⁇ m.
  • Fig.1G shows quantification of KLK5, PAR2, TSLP, and IL33 area in normal and lymphedematous (LE) skin biopsies from patients with unilateral BCRL.
  • Fig.1H shows representative western blots (top) and quantification (bottom; relative to ⁇ -actin) of KLK5 and PAR2 in normal and lymphedematous (LE) skin biopsies from patients with unilateral BCRL.
  • Fig.2A-2C show that expression of keratinocyte growth factors and inflammatory cytokines are upregulated in lymphedema.
  • Fig.2B shows representative immunofluorescent images (top panel) and quantification (bottom panel) of EGF, EGFR, IL1 ⁇ , and NFATc1 area in normal and lymphedematous (LE) skin biopsies from patients with unilateral BCRL. Scale bar: 50 ⁇ m.
  • FIG. 2C shows immunofluorescent analysis of lymphedema skin biopsies with PATENT MSKCC.056.WO1 each antibody (Ab) and respective negative controls without primary antibodies. Scale bar: 50 ⁇ m.
  • Fig.3A-3I show that hyperkeratosis and Th2-inducing cytokine expression have a positive correlation.
  • Fig.3A duration of lymphedema and PAR2
  • Fig.3B Ki67 and EGF
  • Fig.3C Ki67 and EGF
  • Fig.3D KRT14 and TSLP
  • Fig.3D KRT16 and TSLP
  • Fig. 3E EGF and TSLP
  • EGFR and TSLP Fig.3G
  • IL1 ⁇ and IL33 Fig.3H
  • EGFR and IL33 Fig.3I
  • FIG. 4A shows representative H&E (top panel) and immunofluorescent staining for LYVE1 and CD3e (bottom panel) of control (skin incision) tail skin and tail skin harvested 2 or 6 weeks after tail skin and lymphatic excision. Scale bar: 100 ⁇ m.
  • Fig.4C shows representative immunofluorescent images of KRT14, KLK5, PAR2, TSLP, and IL33 staining in tail skin harvested 2 weeks after surgery from control and lymphedema (LE) mice.
  • Fig.5A-5B show no CD4 T cell accumulation in tail skin at two weeks post- surgery.
  • Fig. 5A shows a representative flow cytometry of CD4 + T cells and Th2 cells from tail skin of mice 2 weeks after tail skin and lymphatic excision.
  • Fig.6A-6E show that gene expression changes in keratinocytes occur in rapidly after lymphatic injury and are independent of CD4 T cells.
  • Fig. 6A shows representative immunofluorescent images of KRT6, Ki67, IL1 ⁇ , and NFATc1 staining in tail skin harvested 2 weeks after surgery from control and lymphedema (LE) mice. Scale bar: 100 ⁇ m.
  • Fig.6D shows representative immunofluorescent images of KRT6, KRT14, KLK5, and PAR2 staining in tail specimens harvested 2 weeks after tail skin and lymphatic excision in wild-type (WT) and CD4 knockout (CD4KO) mice. Scale bar: 100 ⁇ m.
  • Fig.7A-7C show that hyperkeratosis and Th2-inducing cytokine expression are increased in a non-surgical model of lymphedema.
  • Fig.7A shows representative H&E and immunofluorescent images of KRT6, Ki67, KLK5, PAR2, TSLP, and IL33 in WT hindlimb skin harvested 9 weeks after DT injection and FLT4CreDTRfloxed hindlimb skin harvested 3 or 9 weeks after DT injection. Scale bar: 100 ⁇ m.
  • Fig.7B shows quantification of epidermal, KRT6, Ki67, KLK5, PAR2, TSLP, and IL33 area in WT hindlimb skin harvested 9 weeks after DT injection and FLT4CreDTRfloxed hindlimb skin harvested 3 or 9 weeks after DT injection.
  • Fig.8A-8G show that PAR2 knockout reduces lymphedema.
  • Fig.8A shows representative gross images of tails from wild-type (WT) and PAR2 knockout (PAR2KO) mice harvested 6 weeks after tail skin and lymphatic excision.
  • Fig.8C shows quantification of CD4 + cells, collagen I, LYVE1 + vessels, and lymphatic vessel diameter in tail skin of WT and PAR2KO mice harvested 6 weeks after tail skin and lymphatic excision.
  • Fig.8D shows representative immunofluorescent images of KLK5, PAR2, TSLP, and IL33 staining in tail skin of WT and PAR2KO mice harvested 6 weeks after tail skin and lymphatic excision. Scale bar: 100 ⁇ m.
  • Fig.8E shows quantification of KLK5, PAR2, TSLP, and IL33 area in tail skin of WT and PAR2KO mice harvested 6 weeks after tail skin and lymphatic excision.
  • Fig.8G shows representative flow cytometry of Langerhans cells and Th2 cells from tail skin and draining lymph nodes (LN) of WT and PAR2KO mice harvested 6 weeks after tail skin and lymphatic excision (left panel). Quantification of the number of Langerhans cells and Th2 cells (right panel).
  • Fig.9A-9C show that PAR2 knockout decreases fibrosis, CD4 + cell infiltration, and hyperkeratosis after lymphatic injury.
  • Fig. 9A shows representative immunofluorescent images of collagen I, LYVE1, and CD4 staining in lymphedema tail skin of wild-type (WT) and PAR2 knockout (PAR2KO) mice harvested 6 weeks after tail skin and lymphatic excision. Scale bar: 100 ⁇ m.
  • Fig.9B shows representative immunofluorescent images (top panel) and quantification (bottom panel) of KRT6, Ki67, and NFATc1 area in tail skin of WT and PAR2KO mice harvested 6 weeks after tail skin PATENT MSKCC.056.WO1 and lymphatic excision. Scale bar: 100 ⁇ m.
  • Fig.10A-10F show that hematopoietic PAR2 expression is not important for development of lymphedema.
  • Fig. 10C shows representative gross images (left panel) and changes in tail volume of tails (right panel) from wild-type (WT) and PAR2 knockout (PAR2KO) mice receiving BM- derived progenitors from CD45.1 mice 6 weeks after tail skin and lymphatic excision.
  • Fig.11C shows representative immunofluorescent images of KRT6, KRT14, Ki67, TSLP, and IL33 staining in mouse tails from mice treated with vehicle (control) or Baicalein for 4 weeks, beginning 2 weeks after tail skin and lymphatic excision.
  • Fig.12A shows representative immunofluorescent images of KRT6, Ki67, KLK5, PAR2, and TSLP staining in h-keratinocytes cultured with PBS (control), lymphatic fluid (LF), or LF+ENMD1068. Scale bar: 20 ⁇ m.
  • Fig.13A-13C show that ENMD1068 decreases keratinocyte activation in response to lymphatic fluid.
  • Fig. 13A shows representative immunofluorescent images of KRT6, Ki67, KLK5, PAR2, and TSLP staining in h-keratinocytes cultured with PBS (control) and lymphatic fluids. Scale bar: 50 ⁇ m.
  • Fig.13B shows quantification of KRT6, Ki67, KLK5, PAR2, and TSLP area in h-keratinocytes cultured with PBS PATENT MSKCC.056.WO1 (control), LF1 or LF2.
  • Each circle represents the average quantification of 2 HPF views for each experiment. P values were calculated by one-way ANOVA.
  • TSLP thymic stromal lymphopoietin
  • a small molecule inhibitor prevents activation of keratinocytes stimulated with lymphedema fluid.
  • lymphedema is a chronic inflammatory skin disease, and that topically targeting keratinocyte activation cam be a clinically effective therapy for this condition.
  • the present invention relates, in part, to the use of a PAR2 inhibitor as a novel, safe, and effective treatment for lymphedema, especially chronic lymphedema.
  • the present invention is based, in part, on the surprising discovery that inhibiting keratinocyte activation and/or proliferation by administering a PAR2 inhibitor markedly improves symptoms of lymphedema, including swelling, fibrosis, and inflammation.
  • the present invention provides compositions and methods for treating or preventing lymphedema, and/or for producing a variety of other beneficial PATENT MSKCC.056.WO1 biological effects including, but not limited to: reduced tissue swelling, reduced lymphatic fluid stasis or “pooling,” reduced tissue fibrosis, reduced tissue inflammation, reduced infiltration of leukocytes, reduced infiltration of macrophages, reduced infiltration of na ⁇ ve and differentiated T-cells, particularly in the skin, reduced collagen deposition and/or scar formation, and/or improved or increased lymphatic function.
  • the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to include A, B, and C; A, B, or C; A or B; A or C; B or C; A and B; A and C; B and C; A (alone); B (alone); and C (alone).
  • SI Système International de Unites
  • lymphedema includes lymphatic tissue fibrosis and lymphatic injury, obstruction, and/or dysfunction. Lymphedema can be primary lymphedema or secondary lymphedema.
  • Lymphedema can include acute lymphedema, chronic lymphedema, congenital lymphedema, post-operative lymphedema, and gradual- onset lymphedema. Symptoms of lymphedema can include swelling, fullness, or puffiness of tissues, inflammation, fibrosis, heaviness, pain, decreased range of motion, aching, recurring infections, skin thickening, and/or discomfort. “Chronic lymphedema” is a disease caused by impaired lymphatic function, and is characterized by fibrosis, chronic inflammation, and/or adipose deposition. Chronic lymphedema has not historically been considered a skin disease.
  • An “active agent” is an agent which itself has biological activity, or which is a precursor or prodrug that is converted in the body to an agent having biological activity.
  • Active agents useful in the methods and compositions of the invention include PAR2 inhibitors and inhibitors of T-helper 2 (Th2)-inducing cytokines.
  • T-helper 2 (Th2)-inducing cytokines are epithelial-derived cytokines that induce production of inflammatory Th2 cytokines. Th2-inducing cytokines include, for example, IL25, IL33, and thymic stromal lymphopoietin (TSLP).
  • an “inhibitor” is an active agent that antagonizes the activity of a target molecule.
  • a “PAR2 inhibitor” antagonizes the activity of PAR2.
  • “Inhibitors,” as used herein, are distinct from active agents that result in reduction of target molecule expression indirectly.
  • an active agent that reduces PAR2 expression via mechanisms outside of antagonizing the PAR2 pathway, such as by inhibiting proliferation of PAR2-expressing cells is not a “PAR2 inhibitor” as used herein.
  • Inhibitors can be, for example, proteins, peptides, peptidomimetics, pepducins, small-molecule compounds, antibodies or antigen-binding fragments thereof, or inhibitory RNAs.
  • PAR2 inhibitors include, for example, peptides such as FSLLRY-NH 2 and LSIGRL-NH2; peptidomimetics such as K-14585, K-12940, and C391; pepducins such as P2pal-18S, PP2pal-14GQ, Z-235, OA-235i, and OA-235c; small-molecule compounds such as ENMD-1068, GB83, GB88, AZ8838, AZ3451, AZ7188, I-191, I-287, anti-PAR2 antibodies such as SAM-11, B5, mAb3949, Fab3949, and MEDI0618.
  • peptides such as FSLLRY-NH 2 and LSIGRL-NH2
  • peptidomimetics such as K-14585, K-12940, and C391
  • pepducins such as P2pal-18S, PP2pal-14GQ, Z-235, OA-235i, and OA-235c
  • ENMD1068 A preferred PAR2 inhibitor for treating or preventing lymphedema is ENMD1068.
  • ENMD1068 refers to N1-3-methylbutyryl-N4-6-aminohexanoyl- PATENT MSKCC.056.WO1 piperazine and its salts. Further PAR2 inhibitors are discussed, for example, in WO 2015/048245. See also references cited by McIntosh et al. (Tables 1 and 2) and by Heuberger et al. (Table 6).
  • PAR2 inhibitor includes, for example, phosphorylated forms and pharmaceutically acceptable salts of the disclosed compounds.
  • Inhibitors of Th2-inducing cytokines include inhibitors of IL25, IL33, and TSLP.
  • IL33 inhibitors include small-molecule compounds such as ZINC08911140, ZINC16933127, ZINC20527417, ZINC40658091, DB00158, and DB00642; anti-IL33 antibodies such as Tozorakimab; and proteins such as IL33trap and H. polygyrus alarmin release inhibitor (HpARI).
  • TSLP inhibitors include small molecule compounds such as Baicalein and its analogs; anti-TSLP antibodies and antigen-binding fragments thereof such as Tezepelumab and Ecleralimab (CSJ117); and proteins, such as those described in WO 2017/174556. 131-134
  • the terms “inhibit,” “block,” and “suppress” are used interchangeably and refer to any statistically significant decrease in biological activity, including full blocking of the activity.
  • subject or “individual” or “patient” is meant a mammalian subject for whom diagnosis, prognosis, or therapy is desired. In a preferred embodiment, the mammalian subject is a human.
  • the subject may have or may have had cancer, for example, a cancer comprising a solid tumor.
  • the subject may have or may have had breast cancer or a cancer affecting male or female reproductive organs, cutaneous system, musculoskeletal system, soft tissues of the extremities or trunk, urinary system, or the head and neck.
  • the subject may have undergone lymph node dissection.
  • the subject has received treatment for cancer, and the lymphedema or lymphatic injury is associated with the cancer treatment or diagnosis.
  • the subject may be receiving or may have received chemotherapy or radiation therapy for cancer treatment or other indications, or may have had one or more lymph nodes surgically removed in the course of cancer treatment or diagnosis.
  • the subject may have sustained a lymphatic injury (for example as the result of removal, ligation or obstruction of lymph nodes or lymph vessels, or fibrosis of lymph tissue), or the subject may have or have had an infection that leads to lymphedema.
  • the infection may be a skin infection or a history of PATENT MSKCC.056.WO1 skin infection(s) that are related to lymphedema or lymphatic injury.
  • the infection may be a parasitic infection that obstructs lymphatic flow or injures the lymphatic system.
  • the subject may have sustained lymphatic injury from joint replacement, trauma, burns, radiation, or chemotherapy. In some instances, obesity can cause injury to the lymphatic system.
  • the lymphedema is primary lymphedema, such as resulting from a congenital abnormality of the lymphatic system.
  • Terms such as “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” refer to therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder.
  • a subject is successfully “treated” for a disease or disorder according to the methods provided herein if the patient shows, e.g., total, partial, or transient alleviation or elimination of symptoms associated with the disease or disorder.
  • treating lymphedema can include, but is not limited to, decreasing swelling, decreasing inflammation, decreasing fibrosis, decreasing pain, increasing range of motion, decreasing heaviness, decreasing tightness, decreasing skin thickening, improving subjective symptoms, and/or improving lymphatic function.
  • Prevent or “prevention” refers to prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder.
  • those in need of prevention include those at risk of or susceptible to developing the disorder.
  • Subjects that are at risk of or susceptible to developing lymphedema include, but are not limited to, cancer patients undergoing radiation therapy, chemotherapy, and/or surgical lymph node dissection.
  • Subjects having acute lymphedema can be at risk for developing chronic lymphedema.
  • a disease or disorder is successfully prevented according to the methods provided herein if the patient develops, transiently or permanently, e.g., fewer or less severe symptoms associated with the disease or disorder, or a later onset of symptoms associated with the disease or disorder, than a patient who has not been subject to the methods of the invention.
  • the pharmaceutical composition of the invention can be administered at any time before or after an event, for example, radiation therapy, chemotherapy, or surgical lymph node dissection, which places a subject at risk of or susceptible to lymphatic injury and/or developing lymphedema.
  • the PATENT MSKCC.056.WO1 pharmaceutical composition is administered prophylactically up to about one week before the event, such as 1, 2, 3, 4, 5, 6, or 7 days before the event. In some instances, the pharmaceutical composition is administered prophylactically on the same day as the event. In some embodiments, the pharmaceutical composition is administered prophylactically within 3 years of the event, for example, within about 1, 2, 3, 4, 5, or 6 days, or within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, or within about 3, 6, 12, 18, 24, 30, or 36 months. In this context, “within” includes time periods before and after the event.
  • the treatment and/or prevention methods described herein may be performed in combination with one or more additional lymphedema treatment and/or prevention methods known in the art, for example, treatment methods involving the administration of other therapeutic agents and/or treatment methods involving surgery, massage, compression therapy, fluid drainage therapy, acupuncture, laser, or any other suitable treatment methods.
  • pharmaceutical composition refers to a preparation that is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components that are unacceptably toxic to a subject to which the composition would be administered.
  • compositions can be in numerous dosage forms, for example, tablet, capsule, liquid, solution, softgel, suspension, emulsion, syrup, elixir, tincture, film, powder, hydrogel, ointment, paste, cream, lotion, gel, mousse, foam, lacquer, spray, aerosol, inhaler, nebulizer, ophthalmic drops, patch, suppository, and/or enema.
  • compositions typically comprise a pharmaceutically acceptable carrier, and can comprise one or more of a buffer (e.g., acetate, phosphate or citrate buffer), a surfactant (e.g., polysorbate), a stabilizing agent (e.g., human albumin), a preservative (e.g., benzyl alcohol), a penetration enhancer, an absorption promoter to enhance bioavailability and/or other conventional solubilizing or dispersing agents.
  • a buffer e.g., acetate, phosphate or citrate buffer
  • a surfactant e.g., polysorbate
  • a stabilizing agent e.g., human albumin
  • a preservative e.g., benzyl alcohol
  • penetration enhancer e.g., an absorption promoter to enhance bioavailability and/or other conventional solubilizing or dispersing agents.
  • Systemic administration means that a pharmaceutical composition is administered such that the active agent enters the circulatory system, for example, via enteral, parenteral, inhalational, or transdermal routes.
  • Enteral routes of administration involve the gastrointestinal tract and include, without limitation, oral, sublingual, buccal, PATENT MSKCC.056.WO1 and rectal delivery.
  • Parenteral routes of administration involve routes other than the gastrointestinal tract and include, without limitation, intravenous, intramuscular, intraperitoneal, intrathecal, and subcutaneous.
  • “Local administration” means that a pharmaceutical composition is administered directly to where its action is desired (e.g., at or near the site of the injury or symptoms).
  • Local routes of administration include, without limitation, topical, inhalational, subcutaneous, ophthalmic, and otic. It is within the purview of one of ordinary skill in the art to formulate pharmaceutical compositions that are suitable for their intended route of administration.
  • An “effective amount” of a composition as disclosed herein is an amount sufficient to carry out a specifically stated purpose. An “effective amount” can be determined empirically and in a routine manner, in relation to the stated purpose, route of administration, and dosage form.
  • administration of the PAR2 inhibitor can comprise systemic administration, at any suitable dose and/or according to any suitable dosing regimen, as determined by one of skill in the art.
  • administration of the PAR2 inhibitor comprises local administration via the topical route.
  • the PAR2 inhibitor can be administered according to any suitable dosing regimen, for example, where the daily dose is divided into two or more separate doses. It is within the skill of the ordinary artisan to determine a dosing schedule and duration for administration.
  • the pharmaceutical composition is administered topically at least once a day or at least twice a day.
  • the pharmaceutical composition is administered subcutaneously at least once a day or at least twice a day.
  • Lymphedema Results in Hyperkeratosis, De-differentiation of Epidermal Cells, and Increased Expression of PAR2 and Th2-Inducing Cytokines
  • RNA sequencing (RNAseq) analysis showed evidence of a Th2 inflammatory response and increased expression of keratins (KRT; Fig.2A) in lymphedematous samples, including KRT6 which is indicative of highly proliferative and activated keratinocytes usually observed only in pathological conditions, 61 and KRT14 which is expressed by mitotically active, less differentiated keratinocytes typically found in the basal layer of the skin. 61,62 Using qPCR, we confirmed KRT6, KRT14, and KRT16 expression were significantly increased in the lymphedematous versus the normal arm, although there was some inter-patient variability (Fig.1B). This variability was not related to the severity or duration of the disease.
  • lymphedema was associated with hyperkeratosis, increased epidermal area, increased number of proliferating Ki67 + keratinocytes, and increased expression of KRT6 and KRT14 (Fig. 1C-1E).
  • KRT6-expressing keratinocytes were enlarged and abnormal in appearance, while KRT14 expression was noted in all layers of the epidermis of lymphedematous arms, indicating decreased differentiation (Fig.1C).
  • These keratinocyte changes correlated with higher expression of keratinocyte growth factors (EGF, EGFR, IL1 ⁇ ) in lymphedematous versus normal skin (Fig.2B).
  • Previously PAR2 was shown as a regulator of Th2-inducing cytokines in AD. PAR2 is activated by serine proteases, such as Kallikrein 5 (KLK5), which cleave N- terminal of the PAR2 molecule to expose the tethered ligand.
  • KLK5 Kallikrein 5
  • Fig.1F-1H KLK5 staining was localized to the cornified layer of the skin, while PAR2, TSLP, and IL33 staining were present and increased in the entire epidermis (Fig.1F).
  • Fig.2C We used negative (no primary antibody) controls to confirm the specificity of our findings.2C).
  • NFATc1 activates the expression of Th2-inducing cytokines by NFATc1 activation
  • 63 we consistently found a significant increase in NFATc1 staining in lymphedematous versus normal skin (Fig.2B).
  • upregulation of PAR2 in lymphedematous skin is positively correlated with the duration of the disease (Fig.3A).
  • Fig.3B, 3C We also found that the expression of Th2-inducing cytokines were significantly and positively correlated with proliferation related genes.
  • the mouse tail model of lymphedema is a surgical procedure, and changes in the epidermis may also reflect wound healing, not just lymphatic injury.
  • DT diphtheria toxin
  • DT diphtheria toxin
  • Topical Inhibition of TSLP Decreases Pathology of Lymphedema [0074] To investigate how Th2-inducing cytokine expressed by keratinocyte contributes lymphedema development, we tested topical Baicalein (5,6,7- trihydroxyflavone), a small molecule inhibitor for TSLP, in vivo in our lymphedema mouse model. We used Aquaphor® ointment as a carrier for Baicalein, based on our prior experience with topical formulations for lymphedema.
  • Th2-inducing cytokine production by keratinocytes was downregulated after Baicalein treatment (Fig.11C).
  • IL1 ⁇ a well-known proinflammatory cytokine
  • Lymphatic Fluid Activates Keratinocyte Proliferation and Cytokine Expression by a PAR2-Dependent Mechanism
  • h-keratinocytes human keratinocytes
  • LF lymphedema fluid
  • Fig.12A, 12B lymphedema fluid
  • keratinocytes are known to play a key role in the pathophysiology of psoriasis and AD, no prior studies have tested the hypothesis that these cells also contribute to the pathology of secondary lymphedema.
  • lymphedema increases the expression of EGF, EGFR, and IL1 ⁇ .
  • both surgical and non-surgical models of lymphedema have the same epidermal changes, indicating that this is independent of wound healing.
  • LF activated h-keratinocyte proliferation and expression of KRT6 in vitro, indicating that soluble factors in lymphedematous tissues regulate keratinocyte changes.
  • our data indicate that lymphatic injury rapidly activates keratinocytes to induce hyperkeratosis in the early stages of lymphedema, and that this is PATENT MSKCC.056.WO1 accompanied by proliferation, inhibited differentiation, and increased expression of stress markers, such as KRT6.
  • lymphatic injury induces lymph fluid accumulation and activates hyperkeratosis accompanied by proliferation and increased keratin6 and keratin14 expression.
  • the expression of KLK5-PAR2 and Th2-inducing cytokines (TSLP, IL33, IL25) are upregulated in keratinocytes of lymphedematous skin, which results in Langerhans cell (LC) activation and Th2 differentiation.
  • TSLP Langerhans cell
  • LC Langerhans cell
  • the MSK IACUC adheres to the National Institutes of Health Public Health Service Policy on Humane Care and Use of Laboratory Animals and operates in accordance with the Animal Welfare Act and the Health Research Extension Act of 1985. Per the IACUC-approved protocol, all mice were maintained in light- and temperature-controlled pathogen-free environments and fed ad libitum. [0086] Adult (8- to 12-week-old) female C57BL/6J mice were used for all treatment studies. We chose to use female mice for our study since secondary lymphedema affects females more commonly than males.
  • PAR2 knockout mice based on a C57BL/6 background were purchased from the Jackson Laboratory (B6.Cg-F2rl1 tm1Mslb /J mice; The Jackson Laboratory, Bar Harbor, ME). Controls were age- and sex-matched wild-type C57B6 mice also purchased from The Jackson Laboratory. Surgical Model of Lymphedema [0087] Anesthesia was induced using isoflurane (Henry Schein Animal Health, Dublin, OH) and mice were kept on a heating blanket to maintain body temperature. Depth of anesthesia was monitored by reaction to pain and observation of respiratory rate. Animals were excluded from the experiment if wound infection or ulceration in the tail was noted at any time point following surgery.
  • DTR mice Lymphatic-specific diphtheria receptor mice were developed as previously described by FLT4-CreERT2 mice (a gift from Sagrario Ortega, CNIO) 114,115 and DTR floxed C57BL/6J mice (C57BL/6-Gt(ROSA)26Sor tm1(HBEGF)Awai /J; The Jackson Laboratory). Cre expression was induced in adult mice by using tamoxifen (300 mg/kg/d intraperitoneally for 3 days) followed by local DT (5 ng subcutaneously daily, 3 doses).
  • Tail volumes (V) were calculated weekly following tail surgery to evaluate the development of lymphedema over time.
  • Digital calipers were used to measure tail diameter every 1 cm starting at the surgical site going distally toward the tip of the tail.
  • Histology and Immunofluorescence [0091] Histological and immunofluorescence analyses were performed using our previously published techniques.
  • H&E and IHC slides were evaluated with brightfield or fluorescent microscopy and scanned using a Mirax slide scanner (Zeiss). Staining was visualized using Pannoramic Viewer (3DHISTECH Ltd., Budapest, Hungary). Epidermal area was quantified in H&E-stained tail cross-sections by measuring the ratio of dark stained epidermis within the total tissue area using MetaMorph Offline software (Molecular Devices, Sunnyvale, CA) with a minimum of 4 high-powered fields per slide by 2 blinded reviewers.
  • RNA sequencing was performed in collaboration with the Integrated Genomics Operation (IGO) Core Facility at MSK. Four pairs of frozen clinical lymphedema/normal skin biopsy specimens were submitted to the IGO. The ribodepletion method was used for RNAseq. mRNA expression was standardized and analyzed by IGO.
  • Real-time qPCR qRT-PCR; ViiA7; Life Technologies, Carlsbad, CA was performed in duplicates using predesigned primer sets (Quantitect Primer Assays, Qiagen, Germantown, MD).
  • the lysates were centrifuged at 13,000 x g for 10 minutes at 4 o C, and protein concentration was measured by BCA protein assay kit (Thermo Fisher Scientific) according to manufacturer’s directions. One to 20 ⁇ g of total protein were separated by NuPAGE TM 4-12% Bis-Tris Gel (Thermo Fisher Scientific) and transferred onto PVDF membranes (Bio-Rad, Hercules, CA).
  • Membranes were blocked with 5% skim milk in TBS containing 0.1% Tween 20 (TBST) at room temperature for 1 hour and incubated with antibodies against KRT6 (ab18586; Abcam), KRT16 (ab154361; Abcam), PAR2 (ab180953; Abcam), KLK5 (MAB7236; R&D system), ⁇ -actin (3700s; Cell signaling) in 0.5% skim milk in TBST at 4 o C overnight. After washing 3 times with TBST, membranes were incubated with HRP-conjugated secondary antibody in TBST at room temperature for 1 hour.
  • ELISA was performed using our published methods. 18 Briefly, tail skin tissue was harvested 1.5 cm distal to the surgical site, flash-frozen in liquid nitrogen, and protein was extracted with tissue extraction protein reagent (ThermoFisher Scientific) mixed with phosphatase and protease inhibitor (Sigma-Aldrich).
  • TSLP mouse ELISA kit EMTSLP; Thermo
  • Mouse IL-33 Quantikine ELISA kit M3300; R&D system. All samples were assessed in triplicate.
  • Flow Cytometry [0097] Flow cytometry was performed to quantify inflammation in the mouse tails after tail surgery.
  • single-cell suspensions were obtained from a 1-cm portion of the tail distal to the surgical site using a combination of mechanical dissociation and enzymatic digestion with a solution of DNase I, Dispase II, collagenase D, and collagenase IV (all Roche Diagnostics; Indianapolis, IN) mixed in 2% fetal calf serum (FCS; Sigma-Aldrich).
  • Rat CD45 (30-F11; #103139), Rat CD45 (30-F11; #103116), Rat CD11b (M1/70; #101228), Armenian hamster CD11c (N418; #117306), Mouse CD207 (4C7; #144206), Rat CD4 (GK1.5; #100408), Armenian hamster CXCR3 (CXCR3-173; #126536), Armenian hamster CCR5 (HM-CCR5; #107016), Armenian hamster CCR4 (2G12; #131214), Rat CCR8 (SA214G2; #150310) from BioLegened (San Diego, CA); Rat F4/80 (BM8; #25-4801-82) from eBioscience (San Diego, CA).
  • DAPI viability stain was also used on all samples to exclude dead cells.
  • Single-stain compensation samples were created using UltraComp eBeads TM (#01-2222-42, Affymetrix, Inc.; San Diego, CA).
  • Flow cytometry was performed using a BD Fortessa flow cytometry analyzer (BD Biosciences) with BD FACS Diva, and data were analyzed with FlowJo software (Tree Star; Ashland, OR).
  • Bone Marrow Transfer [0098] Wild-type and PAR2KO recipient mice received two doses gamma-irradiation 450cFy in Gammacell Exactor 40 (Best Theratronics Ltd, Ottawa, ON Canada) at 4 hours and 0.5 hours prior to transplantation.
  • BM-derived progenitor cells were collected from the femur of CD45.1 donor mice. Each mouse received 1 million BM-derived progenitor PATENT MSKCC.056.WO1 cells through tail vein injection. Two months later, efficiency of BMT was validated by using double staining of CD45.1/CD45.2 In vitro Keratinocyte Culture and Treatment [0099] Human keratinocytes (PCS-200-011; ATCC, VA) were cultured in dermal cell basal medium (PCS-200-030; ATCC) with keratinocyte growth kit (PCS-200-040; ATCC). Keratinocytes were cultured with or without 10% lymphedema fluid in keratinocyte medium.
  • Cells were harvested 6 or 48 hours after the treatment for RNA or protein extraction, respectively.
  • Proliferation of keratinocytes was measured by using Vybrant MTT cell proliferation assay kit (V13154; Thermo).
  • Treatments [00100] Topical formulation of Baicalein (2mM) dissolved in Aquaphor® ointment (Beiersdorf, Hamburg, Germany) was developed in collaboration with the MSK Research Pharmacy Core Facility. Control animals were treated with Aquaphor® ointment alone.
  • Monoclonal antibody against mouse interleukin1 ⁇ (clone ALF-161; 5 ⁇ g/g per dose) or isotype control antibodies (BioXcell, NH, US) were given to mice for 4 weeks intraperitoneally, starting at 2 weeks post- surgery.
  • Statistical Analysis [00102] Statistical analyses were performed using GraphPad Prism 9.0.2 (GraphPad Software, Inc.; San Diego, CA). Samples were assessed for normal distribution using the Shapiro Wilk test. Normally distributed clinical samples were analyzed using paired student’s t-test.
  • T helper 2 differentiation is necessary for development of lymphedema.
  • Savetsky, I.L., et al. Th2 cytokines inhibit lymphangiogenesis.
  • Zampell, J.C., et al. CD4(+) cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis.
  • Tian, W., et al. Leukotriene B4 antagonism ameliorates experimental lymphedema. Sci Transl Med 9(2017). Nakamura, K., Radhakrishnan, K., Wong, Y.M.
  • Hyperkeratosis in human lower limb lymphedema the effect of stagnant tissue fluid/lymph. J Eur Acad Dermatol Venereol 30, 1002-1008 (2016). De Cock, H.E., Affolter, V.K., Wisner, E.R., Ferraro, G.L. & MacLachlan, N.J. Progressive swelling, hyperkeratosis, and fibrosis of distal limbs in Clydesdales, Shires, and Belgian draft horses, suggestive of primary lymphedema. Lymphat Res Biol 1, 191-199 (2003). Carretero, M., et al.
  • Eosinophils changing perspectives in health and disease. Nat Rev Immunol 13, 9-22 (2013). Miyake, K., Shibata, S., Yoshikawa, S. & Karasuyama, H. Basophils and their effector molecules in allergic disorders. Allergy 76, 1693-1706 (2021). Chiricozzi, A., Maurelli, M., Peris, K. & Girolomoni, G. Targeting IL-4 for the Treatment of Atopic Dermatitis. Immunotargets Ther 9, 151-156 (2020). Rothmeier, A.S. & Ruf, W. Protease-activated receptor 2 signaling in inflammation. Semin Immunopathol 34, 133-149 (2012). Athari, S.S.
  • Kallikrein 5 induces atopic dermatitis-like lesions through PAR2- mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 206, 1135-1147 (2009). Zhang, X., Yin, M. & Zhang, L.J. Keratin 6, 16 and 17-Critical Barrier Alarmin Molecules in Skin Wounds and Psoriasis. Cells 8(2019). PATENT MSKCC.056.WO1 Alam, H., Sehgal, L., Kundu, S.T., Dalal, S.N. & Vaidya, M.M. Novel function of keratins 5 and 14 in proliferation and differentiation of stratified epithelial cells.
  • Transgenic mice provide new insights into the role of TGF- alpha during epidermal development and differentiation. Genes Dev 5, 714-727 (1991). Gniadecki, R. Regulation of keratinocyte proliferation. Gen Pharmacol 30, 619-622 (1998). Werner, S. & Smola, H. Paracrine regulation of keratinocyte proliferation and differentiation. Trends Cell Biol 11, 143-146 (2001). PATENT MSKCC.056.WO1 Kobayashi, T., Hashimoto, K., Okumura, H., Asada, H. & Yoshikawa, K. Endogenous EGF-family growth factors are necessary for the progression from the G1 to S phase in human keratinocytes.
  • PARs Protease-activated receptors
  • Th2 cytokines increase Staphylococcus aureus alpha toxin-induced keratinocyte death through the signal transducer and activator of transcription 6 (STAT6).
  • STAT6 signal transducer and activator of transcription 6
  • Vegfr3-CreER (T2) mouse, a new genetic tool for targeting the lymphatic system. Angiogenesis 19, 433-445 (2016). Aschen, S.Z., et al. Lymph node transplantation results in spontaneous lymphatic reconnection and restoration of lymphatic flow. Plast Reconstr Surg 133, 301-310 (2014). Ly, C.L., Kataru, R.P. & Mehrara, B.J. Inflammatory Manifestations of Lymphedema. Int J Mol Sci 18(2017). Garcia Nores, G.D., et al. Regulatory T cells mediate local immunosuppression in lymphedema. J Invest Dermatol 138, 325-335 (2016). Clavin, N.W., et al.
  • TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair.
  • PATENT MSKCC.056.WO1 Zampell, J.C., et al. Lymphatic function is regulated by a coordinated expression of lymphangiogenic and anti-lymphangiogenic cytokines. Am J Physiol Cell Physiol 302, C392-404 (2012). Savetsky, I.L., et al. Lymphatic Function Regulates Contact Hypersensitivity Dermatitis in Obesity. J Invest Dermatol 135, 2742-2752 (2015).
  • Tozorakimab (MEDI3506): an anti-IL-33 antibody that inhibits IL- 33 signalling via ST2 and RAGE/EGFR to reduce inflammation and epithelial dysfunction. Sci Rep 13, 9825 (2023). Liu X., et al. Anti-IL-33 antibody treatment inhibits airway inflammation in a murine model of allergic asthma. Biochem Biophys Res Commun. 386,181-5 (2009). Holgado A., et al. IL-33trap is a novel IL-33-neutralizing biologic that inhibits allergic airway inflammation. J Allergy Clin Immunol. 144, 204-215 (2019). Osbourn M., et al.

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Abstract

L'invention concerne des méthodes et des compositions pour traiter ou prévenir le lymphoedème par administration d'un inhibiteur de la voie du récepteur 2 activé par la protéase (PAR2).
PCT/US2023/033043 2022-09-18 2023-09-18 Inhibition de la voie du récepteur 2 activé par la protéase (par2) pour le traitement et la prévention du lymphoedème WO2024059336A1 (fr)

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Citations (6)

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US20140179903A1 (en) * 2009-09-09 2014-06-26 Regeneron Pharmaceuticals, Inc. High Affinity Human Antibodies to Human Protease-Activated Receptor 2
US20190183818A1 (en) * 2016-08-18 2019-06-20 Memorial Sloan Kettering Cancer Center Inhibition of Sphingosine 1-Phosphate Receptor for Treatment and Prevention of Lymphedema
US20200121634A1 (en) * 2017-01-06 2020-04-23 Korea University Research And Business Foundation, Sejong Campus Pharmaceutical composition for preventing or treating allergic diseases such as asthma or atopy including baicalein as active ingredient
US20200397807A1 (en) * 2019-06-18 2020-12-24 MitoPower, LLC Nicotinyl riboside compounds and their uses
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US20140179903A1 (en) * 2009-09-09 2014-06-26 Regeneron Pharmaceuticals, Inc. High Affinity Human Antibodies to Human Protease-Activated Receptor 2
WO2014082993A2 (fr) * 2012-11-30 2014-06-05 Galapagos Nv Cibles moléculaires et composés, et procédés d'identification de ceux-ci, utiles dans la régulation à la baisse de la réponse th2
US20210069164A1 (en) * 2015-02-05 2021-03-11 Memorial Sloan Kettering Cancer Center Compositions and Methods for Treatment of Edema
US20190183818A1 (en) * 2016-08-18 2019-06-20 Memorial Sloan Kettering Cancer Center Inhibition of Sphingosine 1-Phosphate Receptor for Treatment and Prevention of Lymphedema
US20200121634A1 (en) * 2017-01-06 2020-04-23 Korea University Research And Business Foundation, Sejong Campus Pharmaceutical composition for preventing or treating allergic diseases such as asthma or atopy including baicalein as active ingredient
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