WO2018195772A1 - Pd-1h servant de cible dans le traitement de l'asthme - Google Patents

Pd-1h servant de cible dans le traitement de l'asthme Download PDF

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Publication number
WO2018195772A1
WO2018195772A1 PCT/CN2017/081844 CN2017081844W WO2018195772A1 WO 2018195772 A1 WO2018195772 A1 WO 2018195772A1 CN 2017081844 W CN2017081844 W CN 2017081844W WO 2018195772 A1 WO2018195772 A1 WO 2018195772A1
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asthma
mice
cells
ova
agonist
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PCT/CN2017/081844
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English (en)
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Lieping Chen
Huafeng Liu
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Sun Yat-Sen University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen

Definitions

  • the present invention is related to a method for prophylaxis or treatment of asthma in a subject.
  • the instant invention also concerns use of a PD-1H agonist in the preparation of a pharmaceutical compositions for prophylaxis or treatment of asthma in a subject.
  • Asthma is a common, chronic inflammatory disease of the airways and CD4 + Th2 cells are shown to play critical role in disease induction, pathogenesis and progression.
  • the hallmarks of Th2 type responses in asthma are eosinophilic airway inflammation with mucus secretion, airway remodeling, and hyper-reactivity.
  • IL-5 and IL-13 are critical for the pathophysiology of asthma.
  • IL-5 has multifaceted roles including direct activation of eosinophils, influencing adhesion and inducing chemotaxis and inflammatory mediator synthesis.
  • IL-13 has a major impact in influencing bronchial hyperreactivity, inflammation, and airway remodeling.
  • IL-13 drives epithelial cell maturation and mucus production, synthesis of extracellular matrix proteins and enhanced contractility of airway smooth muscle cells.
  • the mechanisms in the regulation of cytokine production during asthma pathogenesis are yet to be elucidated. Recent therapeutic efforts have focused on blockade of the interaction of these cytokines to their receptors as an approach for asthma treatment.
  • PD-1H (also called Gi24, VISTA, DD1 ⁇ , Dies1) is a cell surface molecule of the B7/CD28 immune modulatory gene family. Alignment of the PD-1H Immunoglobulin V region with CD28 members shows the highest identity with the programmed death one (PD-1) protein. PD-1H is constitutively expressed on the majority of hematopoietic cells including both lymphoid cells (except B cells) and myeloid cells. Several lines of evidence support that PD-1H functions as a coinhibitory receptor on T cells to limit naive T cell activation, whereas PD-1H expressed on antigen-presenting cells (APCs) interacts with an unknown receptor on T cells to suppress T cell responses.
  • APCs antigen-presenting cells
  • PD-1H knockout mice were shown to develop more severe inflammation and autoimmune diseases in several mouse models, indicating a role of PD-1H in the suppression of T cell immunity.
  • agonist monoclonal antibodies (mAb) to mouse PD-1H were shown to suppress T cell–mediated acute hepatitis and prevent acute graft-versus-host disease (GVHD) in semi-and fully allogeneic murine models, leading to full chimerism following treatment. It appears that the effect of PD-1H on the suppression of T cell response could be divided into two stages with an early event in arresting allo-reactive donor T cells from activation and a later event in promoting donor Treg expansion.
  • a method for prophylaxis or treatment of asthma in a subject comprises administering to the subject in need thereof a therapeutically effective amount of a PD-1H agonist.
  • a PD-1H agonist in the preparation of a pharmaceutical composition for prophylaxis or treatment of asthma in a subject.
  • the asthma is a Th2-mediated asthma.
  • the administration is carried out intravenously.
  • the PD-1H agonist is a monoclonal antibody against PD-1H.
  • BALF contains elevated levels of Th2-type cytokines including IL-5 and IL-13 as well as innate inflammatory cytokine MCP-1 and IL-6, as well as increased Th2-like CD4 + T cells and decreased Treg, supporting that PD-1H could function as a negative regulator in the control of airway inflammation in experimental asthma progression.
  • FIG. 1 PD-1H KO mice developed severe lung inflammation and mucus secretion in OVA-induced asthma model.
  • WT and PD-1H KO mice were immunized by i.p. injection of 20 ⁇ g OVA mixed with 4mg aluminum hydroxide gel on day 0 and 5, then challenged with 1%OVA (15ml/20min/day) on 3 consecutive days (12–14) by aerosol instillation. Mice were sacrificed for analyses on day 15.
  • FIG. 3 Blockade of PD-1H enhanced innate and Th2-type cytokine production in OVA-induced asthma.
  • Figure 4 Decreased Treg during experimental asthma induction in PD-1H KO mice.
  • (a) Lung lymphocytes and (b) spleens from the WT and KO mice were collected after the last OVA inhalation, percentage of Foxp3 + CD4 + T cells were analyzed by intracellular staining. **P ⁇ 0.01 and ****P ⁇ 0.0001 (two-tailed Student’s t-test) . All values are expressed as the means ⁇ s.e.m. N 8/group. All experiments were repeated at least 3 times.
  • FIG. 5.4C11 monoclonal antibody and its role in suppressing airway inflammation.
  • (a) PD-1H + CHO cells were stained with mIgG, mam82 and 4C11 and analyzed by flow cytometry.
  • (b, c) Airway inflammation and asthma were induced as described in Figure 1a, but mice were challenged with 1%OVA (25ml/40min/day) on 3 consecutive days (12–14) . Meanwhile, mice were treated by i.p. injection with 200 ⁇ g 4C11 or control mIgG in 200 ⁇ l PBS on day 0, 3, 6, 9 and 12. BALF was collected after the last challenge and stained for leukocyte counts.
  • FIG. 6 Mice at groups of 3 were treated with the plasmid encoding murine PD-1HIg fusion protein by hydrodynamic injection as described previously and sera were sampled daily up to 13 days. The levels of PD-1HIg fusion protein at ng/ml in sera were determined in 3 individual mouse by specific sandwich ELISA with an anti-murine PD-1H mAb MH5A and an anti-human Ig mAb.
  • the terms “treat” or “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the progression of cancer.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable.
  • “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • subject or “individual” or “animal” or “patient” or “mammal, ” is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired.
  • Mammalian subjects include humans, domestic animals, farm animals, and zoo, sport, or pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, and so on.
  • the subject herein is preferably a human.
  • phrases such as “to a patient in need of treatment” or “asubject in need of treatment” includes subjects, such as mammalian subjects, that would benefit from administration of an antibody or composition of the present disclosure used, e.g., for detection, for a diagnostic procedure and/or for treatment.
  • the term "agonist” refers to any agent that increases the level and/or activity of PD-1H.
  • the term “agonist” refers to an agent which increases the expression and/or activity of the PD-1H by at least 10%or more, e.g. by 10%or more, 50%or more, 100%or more, 200%or more, 500%or more, or 1000%or more.
  • Non-limiting examples of agonists of PD-1H can include PD-1H polypeptides or agonist fragments thereof and nucleic acids encoding a PD-1H polypeptide.
  • An aspect of the disclosure provides a method for prophylaxis or treatment of asthma in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a PD-1H agonist, or a pharmaceutical composition comprising the PD-1H agonist.
  • the disclosure provides the PD-1H agonist as described above for use in a method for treating or alleviating symptoms involved with asthma.
  • the PD-1H agonist or the pharmaceutical composition is administered parenterally, e.g. intravenously, intramuscularly, percutaneously or intracutaneously.
  • a PD-1H agonist may be desirable to combine with other agents effective in the treatment of asthma.
  • the treatment of asthma may be implemented with a PD-1H agonist and other anti-asthma therapies, such as ⁇ 2 receptor agonists available in the market.
  • the methods of treating asthma prevent the progression of the infection and/or the onset of disease caused by asthma.
  • a method for preventing the progression of asthma and/or the onset of disease caused by asthma comprises administering an effective amount of a PD-1H agonist to a subject in need thereof.
  • the methods of treating asthma prevent the onset, progression and/or recurrence of a symptom associated with asthma.
  • a method for preventing a symptom associated with asthma in a subject comprises administering an effective amount of a PD-1H agonist to a subject in need thereof.
  • An aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of PD-1H agonist and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is useful for prophylaxis or treatment of asthma in a subject.
  • the PD-1H agonist may be prepared in a suitable pharmaceutically acceptable carrier or excipient.
  • carrier includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like.
  • carrier includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • compositions that do not produce an allergic or similar untoward reaction when administered to a human.
  • pharmaceutically acceptable refers to molecular entities and compositions that do not produce an allergic or similar untoward reaction when administered to a human.
  • aqueous composition that contains a protein as an active ingredient is well understood in the art.
  • injectables either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection can also be prepared.
  • mice All experiments were carried out in accordance with the guidelines of Sun Yat-sen University on animal care and the ethical guidelines for investigation of experimental animals.
  • BALB/c mice were purchased from the Experimental Animal Center of Sun Yat-sen University (Guangzhou, China) .
  • PD-1H KO mice were described previously and were backcrossed with BALB/c mice to generate H-2 d /PD-1H KO strain. Mice in 8–10 weeks old were used for all experiments and kept under specific pathogen-free conditions.
  • PD-1H mAb Generation of PD-1H mAb.
  • Full-length mouse PD-1H-pcDNA3.1 was stably transfected into Chinese hamster ovary cells (CHO cells) by lipofection and the stably transfected PD-1H + CHO cell was confirmed by flow cytometry using mam82 mAb.
  • PD-1H-Ig fusion protein was produced and purified as described.
  • a PD-1H KO mouse was immunized with mouse PD-1H-Ig and the generation of hybridomas secreting PD-1H mAb were performed as described previously. The specificity of the mAb were validated by ELISA and flow cytometry using PD-1H + CHO cell.
  • a clone of PD-1H mAb, 4C11 was selected for further experiments and produced and purified.
  • mice were sensitized by intraperitoneal (i.p. ) injection of 10 ⁇ g OVA (Sigma-Aldrich) with 4mg aluminum hydroxide (Thermo Fisher) gel on days 0 and 5, then challenged with aerosolized 15 or 25 ml 1%OVA for 20 or 40min on days 12, 13, and 14. The aerosol was generated by a nebulizer (NE-U07; Yuyue) . Mice were sacrificed for analyses on day 15. For PD-1H-Ig treatment, groups of mice received hydrodynamic injections intravenously (i.v. ) of 20 ⁇ g PD-1H plasmid in 2ml PBS on days -1, 4 and 11 and the Flag plasmid was the control.
  • mice received i.p. injections of 200 ⁇ g anti-mouse PD-1H mAb (4C11) , on days 0, 3, 6, 9, and 12, or control mouse immunoglobulin G (mIgG) (Rockland) .
  • mIgG mouse immunoglobulin G
  • bronchoalveolar lavage fluid BALF
  • Mice were anesthetized with a lethal dose of pentobarbital and lungs were gently lavaged with 0.5 ml PBS for three times (1.5ml of total BALF) via a tracheal cannula. Samples were centrifuged at 2000 rpm for 5 min. Mouse IL-4, IL-5 and IL-13 in BALF were quantified by ELISA Kits (eBioscience) according to the manufacturer’s protocols, MCP-1 and IL-6 were measured by CBA Kit (BD Bioscience) . The total counts of cells in BALF were determined using a microscope.
  • BALF cells were spun onto microscope slides by CytoFuge and stained with Diff-Quick (Nanjing Jiancheng Bioengineering Institute) , differential cell counts were performed by counting 400 cells per slides using a high-magnification microscope. Sera from experimental mice were collected and OVA-specific IgE was examined by specific sandwich ELISA.
  • lymphocytes were stimulated by 10 ng/ml PMA (Sigma-Aldrich) , 1 ⁇ g/ml ionomycin (Sigma-Aldrich) and Golgi plug (BD Biosciences) for 4hrs and stained with Cytofix/Cytoperm Plus kit (BD Biosciences) .
  • PD-1H is required for suppressing airway inflammation in experimental asthma model
  • WT and PD-1H KO mice were immunized and challenged by OVA to induce asthma (Figure 1a) .
  • Mice were sacrificed at day 15 and differential cell counts were performed in harvested BALF.
  • the challenge by OVA-induced pulmonary infiltration of inflammatory cells in WT mice and inflammatory cells were dominated by eosinophils, also with increased lymphocytes and macrophages.
  • This prominent eosinophilic response is highly characteristic of allergic asthma in this model.
  • PD-1H KO mice had significantly higher total numbers of inflammatory cells in BALF than WT mice, with significant increases of eosinophils. Infiltrating lymphocytes were in a small degree and macrophages were negligible (Figure 1b and c) .
  • mice Similar to PD-1HKO mice, PD-1H-Ig-treated mice showed significantly increased eosinophil counts than that of mice treated with Flag-Ig plasmid control ( Figure 2a and b) , indicating PD-1H-Ig may block PD-1H to interact with its counter-receptor to promote airway inflammation in OVA-induced asthma. Our results thus further support a suppressive role of endogenous PD-1H in the development of lung inflammation during the induction of experimental asthma.
  • CD4 + T helper cell types in lung lymphocytes upon a brief PMA/ionomycin stimulation in vitro by intracellular staining of cytokines.
  • CD4 + IL-4 + Th2-type cells were significantly higher in KO than that of WT mice in the BALF during the asthma induction.
  • the Th1-type cells (CD4 + IFN- ⁇ + ) were significantly less in the KO than that of WT mice ( Figure 3e) .
  • Similar results were also observed in the WT mice treated with PD-1H-Ig vs. control Ig plasmids ( Figure 3f) .
  • mice were administered with 4C11 or control mIgG on day 0, 3, 6, 9 and 12 during the induction of OVA-induced asthma.
  • Mice treated with control IgG developed a typical accumulation of eosinophils in BALF fluid ( Figure 5b and 5c) .
  • the histopathological examination showed massive inflammatory cell infiltration around the bronchi ( Figure 5d) and mucus overproduction into the bronchi ( Figure 5e) .
  • accumulation of eosinophils in BALF was greatly reduced in the 4C11-treated mice ( Figure 5b and 5c) .
  • infiltration of inflammatory cells around the bronchi ( Figure 5d) and overproduction of mucus (Figure 5e) also decreased significantly.
  • IL-5 was originally defined as a T-cell-derived cytokine and now appreciated as a major cytokine to affect many aspects of eosinophils including maturation, differentiation, migration and survival.
  • IL-13 can be produced by various immune and non-immune cells including T cells and eosinophils and could induce airway eosinophilia, airway hyper-responsiveness, and mucus overproduction.
  • IL-4 appears to be less affected by loss of PD-1H, the effect of IL-4 may be replaced by high level of IL-13 because IL-13 and IL-4 share a common ⁇ chain receptor subunit as their receptors and have overlapping biological functions.
  • PD-1H is constitutively found on the surface of T lymphocytes whereas its expression on eosinophils is not yet reported.
  • inflammatory eosinophils isolated from BALF do not express PD-1H. Because both IL-5 and IL-13 could be produced by T cells, it is thus possible that PD-1H on T cells may directly mediate suppression of cytokine production.
  • IL-13 could be produced by various hematopoietic cells while PD-1H is also broadly expressed on the majority of hematopoietic cells. It is thus plausible to speculate that PD-1H may have a more broad suppressive function beyond T cells for IL-13 production from hematopoietic cells in addition to T cells and eosinophils.
  • PD-1H agonist mAbs could suppress acute hepatitis and GVHD in animal models.
  • the treatment could remarkably decrease the number of inflammatory cells in BALF, especially the eosinophils and lymphocytes, as well as pulmonary inflammation and mucus production (Fig. 5) .
  • Our results thus implicate the possibility to target PD-1H for the treatment of allergic diseases.
  • the effect was inconsistent among different experiments (data not shown) .

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Abstract

L'invention concerne une méthode de prévention ou de traitement de l'asthme chez un individu, consistant à administrer à l'individu le nécessitant une quantité thérapeutiquement efficace d'un agoniste de PD-1H.
PCT/CN2017/081844 2017-04-25 2017-04-25 Pd-1h servant de cible dans le traitement de l'asthme WO2018195772A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11306150B2 (en) 2017-01-11 2022-04-19 Bristol-Myers Squibb Company Method of identifying a P-selectin glycoprotein ligand-1 (PSGL-1) antagonist

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103119054A (zh) * 2010-03-26 2013-05-22 达特茅斯大学理事会 Vista调节性t细胞介体蛋白、vista结合剂及其用途
CA2913312A1 (fr) * 2013-05-24 2014-11-27 Medimmune, Llc Anticorps anti-b7-h5 et leurs utilisations
CN104619722A (zh) * 2012-06-22 2015-05-13 达特茅斯大学理事会 新型vista-ig 构建体和vista-ig 用于治疗自身免疫性、过敏性和炎性疾病的用途
WO2015179799A1 (fr) * 2014-05-22 2015-11-26 The General Hospital Corporation Récepteur dd1alpha et ses utilisations dans des troubles immunitaires
CN105246507A (zh) * 2012-09-07 2016-01-13 达特茅斯大学理事会 用于诊断和治疗癌症的vista调节剂
WO2017066561A2 (fr) * 2015-10-16 2017-04-20 President And Fellows Of Harvard College Modulation de pd-1 des lymphocytes t régulateurs pour réguler les réponses immunitaires effectrices des lymphocytes t

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103119054A (zh) * 2010-03-26 2013-05-22 达特茅斯大学理事会 Vista调节性t细胞介体蛋白、vista结合剂及其用途
CN104619722A (zh) * 2012-06-22 2015-05-13 达特茅斯大学理事会 新型vista-ig 构建体和vista-ig 用于治疗自身免疫性、过敏性和炎性疾病的用途
CN105246507A (zh) * 2012-09-07 2016-01-13 达特茅斯大学理事会 用于诊断和治疗癌症的vista调节剂
CA2913312A1 (fr) * 2013-05-24 2014-11-27 Medimmune, Llc Anticorps anti-b7-h5 et leurs utilisations
WO2015179799A1 (fr) * 2014-05-22 2015-11-26 The General Hospital Corporation Récepteur dd1alpha et ses utilisations dans des troubles immunitaires
WO2017066561A2 (fr) * 2015-10-16 2017-04-20 President And Fellows Of Harvard College Modulation de pd-1 des lymphocytes t régulateurs pour réguler les réponses immunitaires effectrices des lymphocytes t

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11306150B2 (en) 2017-01-11 2022-04-19 Bristol-Myers Squibb Company Method of identifying a P-selectin glycoprotein ligand-1 (PSGL-1) antagonist

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