WO2021164107A1 - Il-6受体抗体的新用途 - Google Patents

Il-6受体抗体的新用途 Download PDF

Info

Publication number
WO2021164107A1
WO2021164107A1 PCT/CN2020/082994 CN2020082994W WO2021164107A1 WO 2021164107 A1 WO2021164107 A1 WO 2021164107A1 CN 2020082994 W CN2020082994 W CN 2020082994W WO 2021164107 A1 WO2021164107 A1 WO 2021164107A1
Authority
WO
WIPO (PCT)
Prior art keywords
tocilizumab
patients
patient
injection
treatment
Prior art date
Application number
PCT/CN2020/082994
Other languages
English (en)
French (fr)
Inventor
魏海明
徐晓玲
周永刚
傅斌清
郑小虎
王东升
Original Assignee
中国科学技术大学
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 中国科学技术大学 filed Critical 中国科学技术大学
Publication of WO2021164107A1 publication Critical patent/WO2021164107A1/zh

Links

Images

Classifications

    • 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
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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]
    • C07K16/248—IL-6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration

Definitions

  • the invention belongs to the field of biomedicine, and relates to the application of IL-6 receptor antibody in the preparation of drugs for the treatment of novel coronavirus pneumonia.
  • 2019-nCoV is completely different from the ⁇ -coronavirus related to human severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). It is a new type of coronavirus and belongs to the coronavirus. The virus family is classified into the beta coronavirus 2b lineage; and it is also found that the homology between 2019-nCoV and bat coronavirus is 96%, so it is speculated that bats are the main source (Zhou, P. et al, A pneumonia outbreak associated with a new coronavirus of probable bat origin, Nature Online 3 February 2020).
  • Novel coronavirus patients show features related to cytokine storm
  • Cytokine storm syndrome has attracted more and more attention.
  • Farquhar and Claireaux first proposed the concept of CSS in Familial Hemophagocytic Lymphohistiocytosis (fHLH) in 1952. There was not much research in the following fifty years. Until the SARS outbreak in 2002, CSS caused multiple organ dysfunction (MOF). ), which led to a very high fatality rate, which once again attracted widespread attention (Randy Q. Cron ⁇ Edward M. Behrens et al, Cytokine Storm Syndrome, ISBN 978-3-030-22094-5 (eBook)).
  • MOF multiple organ dysfunction
  • Interleukin-6 is the key node of cytokine storm syndrome (CSS)
  • Interleukin-6 has become a key node of certain cytokine storm syndrome (CSS).
  • IL-6 is a classic multifunctional cytokine involved in inflammation and fever. It has hormone-like properties and affects homeostasis. Disorders of IL-6 production play an important pathological role in a variety of inflammatory diseases.
  • IL-6 receptor has two forms: membrane-bound IL-6 receptor (mIL6R) and soluble IL-6 receptor (sIL-6R).
  • mIL6R membrane-bound IL-6 receptor
  • sIL-6R soluble IL-6 receptor
  • IL-6 binds to sIL-6R to form a complex, and then binds to gp130 on the cell membrane to complete trans-signal transduction and play a pro-inflammatory effect (Simon A. Jones, Jürgen Scheller, and Stefan Rose-John. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. The Journal of Clinical Investigation (2011)).
  • IL-6 receptor antibody tocilizumab can block IL-6R-mediated signal transduction and clinical overview
  • Tocilizumab is a recombinant humanized anti-human IL-6 receptor monoclonal antibody of immunoglobulin IgG1 subtype, which can specifically bind to sIL-6R and mIL-6R, and inhibit sIL-6R and mIL-6R mediation. Signal transduction. Roche and Chugai completed the clinical efficacy and safety studies of intravenous tocilizumab in multiple disease fields including systemic juvenile idiopathic arthritis, adult arthritis and polyarticular juvenile idiopathic arthritis .
  • Intravenous tocilizumab 8mg/kg has been approved for RA (rheumatoid arthritis) in more than 70 countries including Japan and Europe. In the United States, intravenous tocilizumab 4mg/kg and 8mg/kg have been approved for RA patients whose anti-TNF preparations are not effective. In addition, tocilizumab has been approved for the use of giant lymph node hyperplasia in India and Japan.
  • tocilizumab is approved in Japan for the treatment of polyarticular juvenile idiopathic arthritis (pcJIA).
  • pcJIA polyarticular juvenile idiopathic arthritis
  • WA19977 was conducted to examine the effectiveness, safety, PK and PD of tocilizumab in children aged 2-17 years in pcJIA patients.
  • the present invention discloses for the first time that IL-6 receptor antibodies (such as tocilizumab) can be used to treat novel coronavirus pneumonia.
  • IL-6 receptor antibodies such as tocilizumab
  • the present invention provides the following technical solutions:
  • IL-6 receptor antibodies preferably tocilizumab (preferably 350-450 mg, more preferably tocilizumab with a single drug dosage unit of 350-450 mg) are prepared for the treatment of patients suffering from novel coronavirus pneumonia
  • the patient is a mild patient, an ordinary patient, a severe patient or a critically ill patient.
  • the drug or kit further comprises an antiviral preparation and optionally a traditional Chinese medicine preparation, wherein when the IL-6 receptor antibody is present in the kit, the IL- 6 Receptor antibody and antiviral preparations and optionally the Chinese medicine preparations are administered simultaneously, sequentially or separately, wherein the Chinese medicine preparations include but are not limited to Xiyanping injection, Xuebijing injection, Shenfu injection and/or Shengfu injection. Pulse injection.
  • the antiviral agent is ⁇ -interferon (preferably a single drug dosage unit of 5 million U of ⁇ -interferon), lopinavir/ritonavir (preferably, the single-dose unit is 200 mg of lopinavir, and the single-dose unit of ritonavir is 50 mg) or ribavirin (preferably the single-dose unit is 500 mg of ribavirin); wherein
  • the single-administration dose of the interferon- ⁇ is 5 million U doses, twice a day; the single-administration doses of the lopinavir/ritonavir are respectively 200mg/50mg per pill, each 2 times a day; the single administration dose of the ribavirin is 500 mg/time, 2-3 times a day.
  • tocilizumab is 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg or 450 mg, more preferably 400 mg;
  • the tocilizumab is in a form suitable for intravenous infusion.
  • a pharmaceutical composition or a single drug dosage unit (preferably for the treatment of patients with novel coronavirus pneumonia), which contains IL-6 receptor antibody (preferably 350-450mg, more preferably 350mg, 360mg, 370mg, 380mg , 390mg, 400mg, 410mg, 420mg, 430mg, 440mg or 450mg, more preferably 400mg), preferably, the patient is a mild patient, a normal patient, a severe patient or a critical patient.
  • IL-6 receptor antibody preferably 350-450mg, more preferably 350mg, 360mg, 370mg, 380mg , 390mg, 400mg, 410mg, 420mg, 430mg, 440mg or 450mg, more preferably 400mg
  • composition or single-dose unit according to 6 above which further comprises an antiviral agent, and optionally a glucocorticoid.
  • composition or single drug dosage unit according to 6 above which is also used in combination with Chinese medicine preparations, wherein the Chinese medicine preparations include but are not limited to Xiyanping injection, Xuebijing injection, Shenfu injection and / Or Shengmai injection.
  • a product of an intravenous administration device containing IL-6 receptor antibody which administers a fixed dose of IL-6 receptor antibody (preferably tocilizumab) to patients with novel coronavirus pneumonia, and the fixed dose is 350-450 mg , Preferably 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg or 450mg, more preferably 400mg.
  • a method for treating patients with novel coronavirus pneumonia characterized in that 350 mg-450 mg of tocilizumab, preferably 400 mg of tocilizumab are administered to the patient.
  • the selected subjects are patients diagnosed with new coronavirus pneumonia, including but not limited to mild patients, ordinary patients, severe patients or critical patients; and the subject’s serum interleukin 6 (IL -6)
  • IL -6 serum interleukin 6
  • the level is higher than the normal reference interval (the reference interval is ⁇ 7, the unit is pg/ml).
  • the treatment plan for the subject is strictly in accordance with the routine treatment of the "New Coronavirus Pneumonia Diagnosis and Treatment Plan (Fifth Edition or Newer Edition)"; and, in addition to the routine treatment, the subject is given tozhudan Anti-therapeutic, the dose is 350-450 mg, preferably 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg or 450 mg, more preferably the dose is 400 mg, and the infusion time is 1 hour. If fever persists within 12 hours of observation, add another dose (same as before), and the cumulative number of doses is at most 2 times. Do not use it if the body temperature is normal.
  • the IL-6 receptor antibody is a commercially available monoclonal antibody.
  • the IL-6 receptor antibody is a commercially available tocilizumab (for example, purchased from Roche).
  • single drug dosage unit means a single drug dosage form containing IL-6 receptor antibody (especially tocilizumab) to be administered to the patient at the time of the dosing schedule, such as an ampoule (ampoule/ampule), the said ampoule is a small glass container used for containing liquid medicine, the capacity is generally 1-25ml, and it is often used for storing liquid medicine for injection.
  • IL-6 receptor antibody especially tocilizumab
  • the clinical manifestations of novel coronavirus pneumonia are mainly fever, fatigue, and dry cough.
  • a small number of patients have symptoms such as nasal congestion, runny nose, sore throat and diarrhea.
  • Severe patients often develop dyspnea and/or hypoxemia one week after the onset of the disease. In severe cases, they rapidly progress to acute respiratory distress syndrome, septic shock, difficult to correct metabolic acidosis, and coagulation dysfunction. It is worth noting that severe and critically ill patients may have moderate to low fever during the course of their illness, or even no obvious fever. Mild patients only manifested as low-grade fever, mild fatigue, etc., without pneumonia.
  • the chest image of the new coronavirus pneumonia showed multiple small patchy shadows and interstitial changes in the early stage, which were obvious outside the lungs. It then develops into multiple ground glass shadows and infiltration shadows in both lungs. In severe cases, lung consolidation may occur, and pleural effusion is rare.
  • the clinical classification of new coronavirus pneumonia can be divided into:
  • the term "treatment” includes the treatment of disease, and usually also includes slowing down or reversing the progression of the disease, preventing or slowing the onset of one or more symptoms related to the disease, and reducing and/or alleviating the disease.
  • Treatment includes the treatment of disease, and usually also includes slowing down or reversing the progression of the disease, preventing or slowing the onset of one or more symptoms related to the disease, and reducing and/or alleviating the disease.
  • Related to one or more symptoms reducing the severity and/or duration of the disease and/or any symptoms related thereto, and/or preventing the further increase in the severity of the disease and/or any symptoms related thereto, preventing, Reduce or reverse any physiological damage caused by the disease, as well as any pharmacological effects that generally benefit the patient being treated.
  • the present invention proves that patients with novel coronavirus pneumonia can produce high levels of inflammatory factors, including IL-6, GM-CSF and IFN- ⁇ .
  • the treatment plan of "conventional treatment + tocilizumab” on the subject confirmed that the interleukin-6 (IL-6) receptor antibody (such as tocilizumab), especially the specific
  • the dose of tocilizumab can block the inflammatory response of patients with new coronavirus caused by IL-6, which is specifically reflected in one or more of the following improvements: C-reactive protein is significantly reduced; fever response is significantly reduced, and body temperature drops to normal
  • C-reactive protein is significantly reduced
  • fever response is significantly reduced
  • the increase in the number of immune cells is specifically reflected in the significant increase in the number of peripheral white blood cells and lymphocytes, which is conducive to the antiviral response
  • lung damage is reduced, which is specifically reflected in the improvement of oxygenation index.
  • Figure 1 Shows that CD4 + T cells from patients infected with the new coronavirus can produce a high proportion of IL-6, GM-CSF and IFN- ⁇ ;
  • Figure 2 It shows that the peripheral blood mononuclear cells of patients infected with the new coronavirus can highly express IL-6;
  • Figure 3 shows the comparison of body temperature of patients with new coronavirus infection before and after treatment with tocilizumab.
  • Figure 4 Shows CT images of patients with new coronavirus pneumonia before and after tocilizumab treatment.
  • Figure 5 CT scan of the chest, showing that after receiving tocilizumab treatment, both lungs of the patient were significantly relieved.
  • A-C Computed tomography
  • CT showed plaques and ground glass shadows before treatment with tolizumab.
  • D-F Chest CT showed diffuse infiltration in both lungs, but the lesions were significantly absorbed after treatment with tocilizumab.
  • Figures A and D are a 55-year-old male patient. His first symptoms were fever, cough and sputum, and the lesion was absorbed on the 5th day after tocilizumab treatment.
  • Figures B and E show an 82-year-old male patient whose first symptom was fever and absorbed the lesion on the 5th day after tocilizumab treatment.
  • Figures C and F are a 32-year-old male patient. His first symptoms were fever, cough and sputum, and the lesions were absorbed on the 4th day after tocilizumab treatment.
  • FIG. 6 CRP, body temperature, oxygen concentration and oxygen saturation of 21 COVID-19 patients before and after receiving tocilizumab treatment.
  • CRP C-reactive protein
  • FIG. 6 CRP, body temperature, oxygen concentration and oxygen saturation of 21 COVID-19 patients before and after receiving tocilizumab treatment.
  • A After treatment with tocilizumab, C-reactive protein (CRP) was significantly reduced and returned to normal in most patients (16/19, 84.2%).
  • B After treatment with tocilizumab, the fever of all 21 patients returned to normal.
  • CD Before treatment, 20 patients required oxygen therapy, including 9 patients (45.0%) received high-flow oxygen therapy, 7 patients (35.0%) received nasal catheters, and 1 patient (5.0%) received masks. Oxygen, 1 patient (5.0%) received non-invasive ventilation and 2 patients (10.0%) received invasive ventilation.
  • the treatment plan of "tocilizumab + conventional treatment” is adopted for subjects with novel coronavirus pneumonia.
  • the conventional treatment is the conventional treatment defined in accordance with the national “Notice on Printing and Distributing the New Coronavirus Pneumonia Diagnosis and Treatment Plan (Trial Fifth Edition Revised Edition)" Guowei Ban Yihan (2020) No. 117.
  • the conventional treatment includes general treatment, treatment of severe and critical cases, and treatment of traditional Chinese medicine.
  • “general treatment” includes the following regimens:
  • Antiviral treatment There is currently no confirmed effective antiviral treatment.
  • Alpha-interferon aerosol inhalation can be tried (5 million U per adult or equivalent, 2ml of sterile water for injection, 2 times a day), lopinavir/ritonavir (200mg/50mg, each capsule) Take 2 capsules each time, 2 times a day, or add ribavirin (500 mg/time, intravenous infusion 2 to 3 times a day). Pay attention to lopinavir/ritonavir-related diarrhea, nausea, vomiting, liver damage and other adverse reactions, and pay attention to the interaction with other drugs.
  • Antibacterial treatment Avoid blind or inappropriate use of antibacterial drugs, especially the combined use of broad-spectrum antibacterial drugs.
  • treatment of severe and critical cases generally includes the following schemes:
  • Treatment principle On the basis of symptomatic treatment, actively prevent and treat complications, treat underlying diseases, prevent secondary infections, and provide organ function support in a timely manner.
  • Oxygen therapy Severe patients should receive oxygen inhalation with a nasal cannula or mask, and promptly assess whether the respiratory distress and/or hypoxemia is relieved.
  • High-flow nasal catheter oxygen therapy or non-invasive mechanical ventilation When the patient's respiratory distress and/or hypoxemia cannot be relieved after receiving standard oxygen therapy, high-flow nasal catheter oxygen therapy or non-invasive ventilation can be considered. If the condition does not improve or worsens within a short period of time (1-2 hours), tracheal intubation and invasive mechanical ventilation should be performed in time.
  • Invasive mechanical ventilation use lung protective ventilation strategy, namely small tidal volume (4-8ml/kg ideal body weight) and low inspiratory pressure (platform pressure ⁇ 30cmH 2 O) for mechanical ventilation to reduce ventilator-related lungs damage. Many patients have asynchrony between man and machine, so sedation and muscle relaxants should be used in time.
  • ARDS severe acute respiratory distress syndrome
  • prone ventilation should be performed for more than 12 hours a day. If the prone position is not effective, extracorporeal membrane oxygenation (ECMO) should be considered as soon as possible if conditions permit.
  • ECMO extracorporeal membrane oxygenation
  • Circulation support On the basis of adequate fluid resuscitation, improve microcirculation, use vasoactive drugs, and perform hemodynamic monitoring when necessary.
  • Glucocorticoids can be used in a short period of time (3 to 5 days) according to the patient’s dyspnea and chest imaging progress. The recommended dose should not exceed the equivalent of methylprednisolone 1-2mg/kg/day, and attention should be paid to larger doses of sugar. Corticosteroids can delay the elimination of coronavirus due to immunosuppressive effects; Xuebijing can be administered intravenously 100ml/time, twice a day; intestinal microecological regulators can be used to maintain intestinal microecological balance and prevent secondary occurrence Bacterial infection; convalescent plasma treatment can be used; for critically ill patients with high inflammation, extracorporeal blood purification technology can be considered if conditions permit.
  • Chinese medicine treatment generally includes the following schemes:
  • Clinical manifestation 1 fatigue with gastrointestinal discomfort
  • Clinical manifestations chills, fever or no fever, dry cough, dry throat, fatigue, chest tightness, swelling, or nausea, loose stools.
  • the tongue is pale or reddish, the fur is white and greasy, and the pulse is smooth.
  • Clinical manifestations body heat does not return or there is cold and heat, less cough and sputum, or yellow phlegm, abdominal distension and constipation. Chest tightness, shortness of breath, coughing and wheezing, and wheezing when moving. Red tongue, yellow greasy or dry fur, slippery pulse.
  • Clinical manifestations Difficulty breathing, frequent wheezing or need for assisted ventilation, accompanied by dizziness, irritability, sweating, cold limbs, dark purple tongue, thick or dry fur, floating pulse without roots.
  • Flow cytometry was used to detect the proportion, absolute number and phenotypic molecules of peripheral blood immune cells in 33 patients with novel coronavirus pneumonia (including 12 severe ICU patients and 21 ordinary patients) and 10 normal people.
  • Interferon- ⁇ (IFN ⁇ ), colony stimulating factor (GM-CSF) and IL-6 the main factors of inflammatory storms.
  • IFN ⁇ Interferon- ⁇
  • GM-CSF colony stimulating factor
  • IL-6 the main factors of inflammatory storms.
  • the results showed that compared with normal people in the control group, in patients with new coronavirus pneumonia, fresh The CD4 + T cells still produce a high proportion of GM-CSF, IFN- ⁇ and IL-6, and the expression level is higher in ICU severe patients (see Figure 1).
  • Example 2 The expression of IL-6 in monocytes of subjects
  • Flow cytometry was used to detect the proportion, absolute number and phenotypic molecules of peripheral blood immune cells in the 33 cases of novel coronavirus pneumonia patients (including 12 severe ICU patients and 21 ordinary patients) and 10 normal people.
  • monocytes are an important part of peripheral immune cells.
  • the main factor IL-6 of cytokine storm was detected by the flow cytokine method of internal standardization. Compared with normal people in the control group, it was found that in patients with new coronavirus pneumonia, CD4 + Monocytes (monocytes) produce a high proportion of IL-6. Importantly, in severe patients in the ICU, these inflammatory monocytes are also Secreted high levels of IL-6, exacerbating the cytokine storm (see Figure 2). The above illustrates that IL-6 is a key immunotherapy target.
  • the drug "tocilizumab” injection for rheumatic diseases can block the interleukin-6 pathway.
  • Document No. 117, Guoweibanyihan (2020), the First affiliated Hospital of the University of Science and Technology of China and the Second People’s A total of 6 patients in the hospital were clinically classified, including 1 case of general type and 5 cases of severe type.
  • the new treatment plan of "tocilizumab + conventional treatment” was adopted; among them, the conventional treatment was based on the national “Regarding the issuance of new coronaviruses”.
  • Pneumonia diagnosis and treatment plan (trial implementation of the fifth revised version) notice "Guoweiban Yihan (2020) No. 117 defines conventional treatment.
  • the 6 patients in this example have undergone 4-10 days of conventional treatment, 7 patients still have typical lesions in both lungs, and 6 patients all showed high fever (average fever time was 7.8 days, average body temperature reached 38.3°C), Among the 6 cases, 2 cases of white blood cells were lower than the normal reference interval (reference interval was 3.5-9.5, unit is ⁇ 10 9 /L), and all lymphocyte counts of 6 cases were lower than the normal reference interval (reference interval was 1.1-3.2, unit was ⁇ 10 9 /L), all serum interleukin 6 (IL-6) levels in 6 cases were higher than the normal reference interval (reference interval was ⁇ 7, unit pg/ml), and all serum C-reactive protein levels in 6 cases were higher than normal The reference interval (reference interval is ⁇ 8, unit mg/l), all oxygenation indexes of 6 cases are lower than the normal reference interval (reference interval 400-500, unit mmhg) as shown in Table 1.
  • the blood index changes of the 6 subjects are shown in Table 1.
  • the number of white blood cells and/or lymphocytes increased in 5 patients, indicating that the body's immune function is recovering and antiviral ability is improving; 6 patients' C-reactive protein decreased, indicating that the body's inflammatory response has decreased, and the cytokine storm has decreased; at the same time, The oxygenation index of 5 patients improved compared with before (see Table 1).
  • IL6 is a cytokine and requires its receptor (IL6 receptor) to exert its effector function.
  • Tocilizumab targets the IL6 receptor, blocking the binding of IL6 to its receptor, and achieves the effect of blocking the function of IL6.
  • IL6 cannot bind to its receptor, and IL6 will not be consumed and accumulated in the body, so the blood IL6 level will increase after treatment; but even if it rises, the body has the presence of tocilizumab at this time , It also cannot play an effect function.
  • Example 4 Tocilizumab treatment of patients with new coronary pneumonia
  • a severe diagnosis is defined: (1) Respiratory rate ⁇ 30 breaths/minute; (2) SpO2 ⁇ 93% when breathing indoor air; (3) )PaO2/FiO2 ⁇ 300mmHg. If there is any of the following conditions, it is diagnosed as a critical case: (1) Respiratory failure that requires mechanical ventilation; (2) Shock; (3) Combined with other organ failure, you need to enter the ICU.
  • IL-6 is measured by electrochemiluminescence (Roche Diagnostics GmbH) or FACS analysis. Without adding any re-stimulation, intracellular staining of IL-6 was performed. Then the cells were collected, washed and blocked according to eBioscience's instructions. The normal range of IL-6 is less than 7pg/ml.
  • the average age of the subjects was 56.8 ⁇ 16.5 years, and the range was 25 to 88 years (Table 2).
  • 21 patients 18 males (85.7%) and 3 females (14.3%).
  • Seventeen patients (81.0%) were assessed as severe and 4 patients (19.0%) were assessed as critical.
  • 5 patients (23.8%) had a history of exposure, and 6 patients (28.6%) had patients who had been exposed to confirmed COVID-19.
  • the white blood cell count showed that 4 patients (4/20, 20.0%) had abnormal values in the peripheral blood (average 6.30 ⁇ 2.77 ⁇ 10 9 /L). (table 3). The percentage of lymphocytes was reduced in 85.0% of patients (17/20, with an average of 15.52 ⁇ 8.89%). C-reactive protein (CRP) levels increased in all 20 patients (average 75.06 ⁇ 66.80 mg/L). The median procalcitonin (PCT) value was 0.33 ⁇ 0.78 ng/mL, and only 2 (10.0%) of 20 patients showed abnormal values. In addition, before tocilizumab treatment, all patients were analyzed for IL-6 expression levels, with an average of 132.38 ⁇ 278.54pg/ml, which showed that IL-6 was up-regulated in these severe and critical COVID-19 patients.
  • CT scans showed that 19 patients (90.5%) had absorbed the lesions, and other patients had a little improvement (the CT scans before and after treatment are shown in Figure 5A-C and Figure 5D-F).
  • tocilizumab can effectively treat severe COVID-19 patients, which may be due to the blocking of IL-6-related fever and inflammatory storm response.
  • CHD coronary heart disease
  • COPD chronic obstructive pulmonary disease
  • CKD chronic kidney disease.
  • the data are n/N (%).
  • Table 4 Body temperature (°C) of patients before and after tocilizumab treatment
  • Table 5 IL-6 levels before and after tocilizumab treatment
  • Table 7 Lymphocyte count before and after tocilizumab treatment
  • Table 8 White blood cell count before and after tocilizumab treatment
  • the IL-6 receptor antibody tocilizumab especially 400mg tocilizumab, achieves one or more of the following effects: C-reactive protein is significantly reduced; fever response is significantly reduced, and body temperature drops to normal; The increase in the number of immune cells is embodied in a significant increase in the number of peripheral white blood cells and lymphocytes, which is conducive to the antiviral response; lung damage is reduced, which is embodied in the improvement of oxygenation index, which has a good effect on the treatment of new coronavirus pneumonia.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Virology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Zoology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

本发明提供了IL-6受体抗体(例如托珠单抗)在制备用于治疗新型冠状病毒肺炎的药物中的用途。本发明还提供了一种用于治疗新型冠状病毒肺炎的药物组合物，其含有IL-6受体抗体(例如托珠单抗)，以及药学上可接受的载体或辅料。IL-6受体抗体能够改善氧合指数，降低受试者的体温。

Description

IL-6受体抗体的新用途 技术领域
本发明属于生物医药领域，涉及IL-6受体抗体在制备用于治疗新型冠状病毒肺炎的药物中的应用。
背景技术
1.关于新型冠状病毒的介绍：
[根据细则26改正19.06.2020]　
研究人员通过全基因组测序和系统发育分析表明，2019-nCoV与人类严重急性呼吸综合征(SARS)和中东呼吸综合征(MERS)相关的β冠状病毒截然不同，是一种新型冠状病毒，属于冠状病毒家族，并被归类于beta冠状病毒2b谱系；并且还发现2019-nCoV与蝙蝠冠状病毒的同源性为96％，因此推测蝙蝠是主要来源(Zhou，P.et al，A pneumonia outbreak associated with a new coronavirus of probable bat origin，Nature Online 3 February 2020)。2020年2月11日，国际病毒分类委员会(International Committee on Taxonomy of Viruses，ICTV)宣布，新型冠状病毒(2019-nCoV)的正式分类名为严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2，SARS-CoV-2)。同日，世界卫生组织(WHO)宣布，由这一病毒导致的疾病正式名称为“COVID-19”。
2.新型冠状病毒患者表现细胞因子风暴相关的特征
细胞因子风暴综合征(CSS)越来越引起大家的关注。Farquhar和Claireaux于1952年在家族性噬血细胞淋巴组织细胞增生症(fHLH)中首次提出CSS概念，之后的五十年里研究并不多，直到02年SARS爆发， CSS引起多器官功能不全(MOF)，导致极高的致死率，才再次引起了广泛关注(Randy Q.Cron·Edward M.Behrens et al，Cytokine Storm Syndrome，ISBN 978-3-030-22094-5(eBook))。
[根据细则26改正19.06.2020]　
CSS的标志是一种不受控制和功能失调的免疫反应，涉及淋巴细胞和单核细胞等的持续激活和扩增，它们分泌大量的炎症相关因子。ICU(重症监护)患者与非ICU患者之间的进一步比较表明，ICU患者的IL2，IL7，IL10，GCSF，IP10，MCP1，MIP1A和TNFα的血浆浓度高于非ICU患者，这表明细胞因子风暴与疾病严重程度有关(Chaolin Huang et al，Clinical features of patients infected with 2019 novel coronavirus in Wuhan，China，Lancet January 24，2020)。新型冠状病毒患者的临床症状也呈现为细胞因子风暴相关特征，表现为发热、肝功能不全、淋巴细胞减少、凝血病、肾脏毒性等，并且预示了不良的临床结果。寻找能够有效控制“炎症因子风暴”治疗方法，阻止病情向重症发展是减少重症、危重症发生、降低死亡率的重要策略。
3.白细胞介素-6(IL-6)是细胞因子风暴综合征(CSS)的关键节点
白细胞介素-6(IL-6)已成为某些细胞因子风暴综合征(CSS)的关键节点。IL-6是一种经典的多功能细胞因子，参与炎症反应和发热反应，具有类似激素的特性，影响体内稳态。IL-6产生失调在多种炎症性疾病中发挥重要的病理作用。IL-6受体具有膜结合IL-6受体(mIL6R)和可溶性IL-6受体(sIL-6R)两种形式。IL-6与sIL-6R结合形成复合物，进而与细胞膜上gp130结合，完成反式信号转导，发挥促炎作用(Simon A.Jones，Jürgen Scheller，and Stefan Rose-John.Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling.The Journal of Clinical Investigation(2011))。
4.IL-6受体抗体托珠单抗可以阻断IL-6R介导的信号转导和临床概况
托珠单抗是免疫球蛋白IgG1亚型的重组人源化抗人IL-6受体单克隆抗体，可以特异性结合sIL-6R和mIL-6R，并抑制sIL-6R和mIL-6R介导的信号转导。Roche和Chugai在包括系统性幼年特发性关节炎、成年型关节炎和多关节型幼年特发性关节炎的多个疾病领域开展完成了静脉内托珠单抗的临床有效性和安全性研究。
静脉内的托珠单抗8mg/kg已在包括日本和欧洲的超过70个国家被批准用于RA(类风湿性关节炎)。在美国，静脉注射托珠单抗4mg/kg和8mg/kg已被批准用于对抗TNF制剂效果不佳的RA患者。此外，托珠单抗已在印度和日本被批准用于巨大淋巴结增生。
2011年4月15日，美国食品与药品监理署(U.S.Food and Drug Administration)批准单独使用托珠单抗或与氨基嘌呤联合治疗活性系统性幼年特发性关节炎(sJIA)(TCZ ACTEMRA的US Package Insert(USPI)，2011年4月)。2011年8月1日，托珠单抗在欧洲批准用于治疗对NSAID和全身性皮质类固醇治疗不佳的sJIA，托珠单抗可以在2岁及以上的患者中进行单独治疗或与MTX联合治疗(RoACTEMRA的产品特征摘要，Roche Resistration Limited 6 Falcon Way Shire Park，Welwyn Garden City，AL71TW，英国，2010年6月4日)。批准的剂量为体重小于30kg的sJIA患者，每2周静脉注射一次12mg/kg；体重大于等于30kg的患者，每两周静脉注射8mg/kg。
基于在日本进行的3期临床研究MRA318JP，托珠单抗在日本批准用于治疗多关节型幼年特发性关节炎(pcJIA)。另外，进行的WA19977的3期研究，考查了托珠单抗在pcJIA患者中年龄为2-17岁儿童的有效性、安全性、PK和PD。
发明内容
本发明首次公开了IL-6受体抗体(例如托珠单抗)可用于治疗新型冠状病毒肺炎。具体地，本发明提供了以下技术方案：
1.IL-6受体抗体，优选托珠单抗(优选350-450mg，更优选单次药物剂量单元为350-450mg的托珠单抗)在制备用于治疗患有新型冠状病毒肺 炎的患者的药物或试剂盒中的用途，优选地，所述患者为轻型患者，普通型患者，重型患者或危重型患者。
2.根据上述1所述的用途，其中所述药物或试剂盒进一步包含抗病毒制剂和任选地中药制剂，其中当所述IL-6受体抗体存在于试剂盒中时，所述IL-6受体抗体与抗病毒制剂和任选地所述中药制剂同时、依次或分别施用，其中所述中药制剂包括但不限于喜炎平注射剂、血必净注射剂、参附注射液和/或生脉注射液。
3.根据上述2所述的用途，其中，所述抗病毒制剂为α-干扰素(优选单次药物剂量单元为500万U的α-干扰素)、洛匹那韦/利托那韦(优选单次药物剂量单元为200mg的洛匹那韦，单次药用剂量单元的利托那韦为50mg)或利巴韦林(优选单次药物剂量单元为500mg的利巴韦林)；其中
优选地，所述α-干扰素的单次施用剂量为500万U剂量，每日2次；所述洛匹那韦/利托那韦的单次施用剂量分别为200mg/50mg每粒，每日2次；所述利巴韦林的单次施用剂量为500mg/次，每日2-3次。
4.根据前述任一项所述的用途，其中，所述IL-6受体抗体为托珠单抗。
5.根据上述4所述的用途，其中，所述托珠单抗的单次施用剂量为350mg，360mg，370mg，380mg，390mg，400mg，410mg，420mg，430mg，440mg或450mg，更优选400mg；优选地，所述托珠单抗为适于静脉输注的形式。
6.一种药物组合物或单次药物剂量单元(优选用于治疗新型冠状病毒肺炎的患者)，其含有IL-6受体抗体(优选350-450mg，更优选为350mg，360mg，370mg，380mg，390mg，400mg，410mg，420mg，430mg，440mg或450mg，进一步优选400mg)，优选地，所述患者为轻型患者，普通型患者，重型患者或危重型患者。
7.根据上述6所述的药物组合物或单次药物剂量单元，其还包含抗病毒制剂，以及任选地糖皮质激素。
8.根据上述7所述的药物组合物或单次药物剂量单元，其中，所述抗病毒制剂为α-干扰素、洛匹那韦/利托那韦或利巴韦林。
9.根据上述6-8任一项所述的药物组合物或单次药物剂量单元，其中，所述IL-6受体抗体为托珠单抗。
10.根据上述6所述的药物组合物或单次药物剂量单元，其还与中药制剂联用，其中所述中药制剂包括但不限于喜炎平注射剂、血必净注射剂、参附注射液和/或生脉注射液。
11.包含IL-6受体抗体的静脉施用器械的制品，其向新型冠状病毒肺炎的患者施用固定剂量的IL-6受体抗体(优选托珠单抗)，所述固定剂量为350-450mg，优选为350mg，360mg，370mg，380mg，390mg，400mg，410mg，420mg，430mg，440mg或450mg，更优选400mg。
12.治疗新型冠状病毒肺炎的患者的方法，其特征在于给予所述患者350mg-450mg的托珠单抗，优选400mg托珠单抗。
13.项目12所述的治疗新型冠状病毒肺炎的患者的方法，其中所述托珠单抗与抗病毒药物(如α-干扰素、洛匹那韦/利托那韦或利巴韦林)和/或抗炎药(如甲泼尼龙)联合使用。
在本发明中，所选用的受试者为确诊新型冠状病毒肺炎的患者，包括但不限于轻型患者、普通型患者、重型患者或危重型患者；并且受试者的血清白细胞介素6(IL-6)水平高于正常参考区间(参考区间为＜7，单位pg/ml)。
在本发明中，对受试者的治疗方案严格按照《新型冠状病毒肺炎诊疗方案(第五版或更新版)》的常规治疗；并且，除了给予常规治疗以外，对受试者给予托珠单抗治疗，剂量为350-450mg，优选350mg，360mg，370mg，380mg，390mg，400mg，410mg，420mg，430mg，440mg或450mg，更优选剂量为400mg，输注时间为1小时。观察12小时内如仍有发热，再追加一次剂量(同前)，累计给药次数最多为2次。如体温正常则不再使用。
本发明的术语
在本发明中，IL-6受体抗体为商购的单克隆抗体。具体地，所述IL-6受体抗体为商购的托珠单抗(例如购自罗氏)。
在本发明中，术语“单次药物剂量单元”表示在给药方案的时刻待给药于病人的包含IL-6受体抗体(特别是托珠单抗)的单次药物剂型，如安瓿瓶(ampoule/ampule)，所述安瓿瓶是用于盛装药液小型玻璃容器，容量一般为1～25ml，常用于存放注射用药液。
在本发明中，新型冠状病毒肺炎的临床表现以发热、乏力、干咳为主要表现。少数患者伴有鼻塞、流涕、咽痛和腹泻等症状。重症患者多在发病一周后出现呼吸困难和/或低氧血症，严重者快速进展为急性呼吸窘迫综合征、脓毒症休克、难以纠正的代谢性酸中毒和出凝血功能障碍等。值得注意的是重型、危重型患者病程中可为中低热，甚至无明显发热。轻型患者仅表现为低热、轻微乏力等，无肺炎表现。
在实验室检查中，新型冠状病毒肺炎发病早期外周血白细胞总数正常或减少，淋巴细胞计数减少，部分患者可出现肝酶、乳酸脱氢酶(LDH)、肌酶和肌红蛋白增高；部分危重者可见肌钙蛋白增高。多数患者C反应蛋白(CRP)和血沉升高，降钙素原正常。严重者D-二聚体升高、外周血淋巴细胞进行性减少。在鼻咽拭子、痰、下呼吸道分泌物、血液、粪便等标本中可检测出新型冠状病毒核酸。
新型冠状病毒肺炎的胸部影像早期呈现多发小斑片影及间质改变，以肺外带明显。进而发展为双肺多发磨玻璃影、浸润影，严重者可出现肺实变，胸腔积液少见。
新型冠状病毒肺炎的临床分型可分为：
(1)轻型。临床症状轻微，影像学未见肺炎表现。
(2)普通型。具有发热、呼吸道等症状，影像学可见肺炎表现。
(3)重型。符合下列任何一条：呼吸窘迫，M＞30次/分；静息状态下，指氧饱和度≤93％；动脉血氧分压(PaO 2)/吸氧浓度(FiO 2)≤300mmHg(1mmHg＝0.133kPa)。
(4)危重型。符合以下情况之一者：出现呼吸衰竭，且需要机械通气；出现休克；合并其他器官功能衰竭需ICU监护治疗。
在本发明中，术语“治疗”包括治疗疾病，而且通常还包括减慢或逆转疾病的进展，预防或减慢与疾病有关的一种或更多种症状的发作，减少和/或减轻与疾病有关的一种或更多种症状，减少疾病和/或与其有关的任 何症状的严重性和/或持续时间和/或预防疾病和/或与其相关的任何症状的严重程度的进一步增加，预防、减少或逆转由疾病引起的任何生理损害，以及通常有益于正在治疗的患者的任何药理作用。
本发明的技术效果：
本发明证实了新型冠状病毒肺炎患者体内可产生高水平的炎症因子，包括IL-6、GM-CSF和IFN-γ。
在本发明中，通过对受试者进行“常规治疗+托珠单抗”的治疗方案，证实了白细胞介素-6(IL-6)受体抗体(例如托珠单抗)，特别是特定剂量的妥珠单抗能够阻断IL-6引起的新型冠状病毒患者的炎症反应，具体体现为下述一种或多种的改善：C反应蛋白明显下降；发热反应明显降低，体温降至正常；免疫细胞数量增加，具体体现为外周白细胞和淋巴细胞数量明显回升，其有利于抗病毒反应；肺脏损伤减少，具体体现为氧合指数得到改善。
附图说明
图1：显示了新型冠状病毒感染患者的CD4 +T细胞可产生高比例的IL-6、GM-CSF和IFN-γ；
图2：显示了新型冠状病毒感染患者的外周血单核细胞可高表达IL-6；
图3：显示了新型冠状病毒感染患者在接受托珠单抗治疗前和治疗后的体温对比。
图4：显示托珠单抗治疗前后新型冠状病毒肺炎患者的CT影像图。
图5：为胸部CT扫描，显示了在接受托珠单抗治疗后，患者双肺均显著缓解。(A-C)在用托利珠单抗治疗之前，计算机断层摄影(CT)显示斑块状和磨玻璃影。(D-F)胸部CT显示在双肺中都有扩散浸润，但在使用托珠单抗治疗后病灶明显吸收。图A、D为55岁男性患者，其第一症状表现为发热、咳嗽和痰，并且在托珠单抗治疗之后第5天吸收了病灶。图B和E为82岁男性患者，其第一症状表现为发热，并且在托珠单抗治疗后第5天吸收了病灶。图C和F为32岁男性患者，其第一症状表现为发热、咳嗽和痰，并且在托珠单抗治疗后第4天吸收了病灶。
图6：为接受托珠单抗治疗之前和之后，21例COVID-19患者的CRP、体温、吸氧浓度和氧饱和度的值。(A)在用托珠单抗治疗之后，在大多数患者(16/19，84.2％)中C-反应蛋白(CRP)显著降低并恢复正常。(B)在用托珠单抗治疗之后，所有21例患者的发热恢复正常。(C-D)在治疗前，20例患者需要氧疗，其中包括9例患者(45.0％)为高流量氧疗、7例患者(35.0％)为鼻导管、1例患者(5.0％)为面罩给氧、1例患者(5.0％)为无创通气和2例患者(10.0％)为有创通气。在托珠单抗治疗之后，15例患者(75.0％)在托珠单抗之后降低了他们的氧摄入，并且氧饱和度保持稳定。其中，1例患者在第三天不需要接受进一步的氧疗，因此吸氧浓度已标记为21％，与正常空气中的氧气含量相似。图6B-D使用成对t检验分析。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明白，以下结合具体实施例，并参照附图，对本发明作进一步的详细说明。
下述实施例中所用方法如无特别说明均为常规方法，所用的试剂如无特别说明均为可商购的试剂。
在本发明的具体实施方案中，对新型冠状病毒肺炎受试者采用“托珠单抗+常规治疗”的治疗方案。其中，所述的常规治疗为根据国家“关于印发新型冠状病毒肺炎诊疗方案(试行第五版修正版)的通知”国卫办医函(2020)117号所定义的常规治疗。具体地，所述常规治疗包括一般治疗、重型、危重型病例的治疗和中医治疗。
在本发明的具体实施方案中，“一般治疗”包括以下方案：
1.卧床休息，加强支持治疗，保证充分热量；注意水、电解质平衡，维持内环境稳定；密切监测生命体征、指氧饱和度等。
2.根据病情监测血常规、尿常规、CRP、生化指标(肝酶、心肌酶、肾功能等)、凝血功能、动脉血气分析、胸部影像学等。有条件者可行细胞因子检测。
3.及时给予有效氧疗措施，包括鼻导管、面罩给氧和经鼻高流量氧疗。
4.抗病毒治疗：目前没有确认有效的抗病毒治疗方法。可试用α-干扰素雾化吸入(成人每次500万U或相当剂量，加入灭菌注射用水2ml， 每日2次)、洛匹那韦/利托那韦(200mg/50mg，每粒)每次2粒，每日2次，或可加用利巴韦林(500mg/次，每日2至3次静脉输注)。要注意洛匹那韦/利托那韦相关腹泻、恶心、呕吐、肝功能损害等不良反应，同时要注意和其他药物的相互作用。
5.抗菌药物治疗：避免盲目或不恰当使用抗菌药物，尤其是联合使用广谱抗菌药物。
在本发明的具体实施方案中，“重型、危重型病例的治疗”一般包括以下方案：
1.治疗原则：在对症治疗的基础上，积极防治并发症，治疗基础疾病，预防继发感染，及时进行器官功能支持。
2.呼吸支持：
(1)氧疗：重型患者应当接受鼻导管或面罩吸氧，并及时评估呼吸窘迫和(或)低氧血症是否缓解。
(2)高流量鼻导管氧疗或无创机械通气：当患者接受标准氧疗后呼吸窘迫和(或)低氧血症无法缓解时，可考虑使用高流量鼻导管氧疗或无创通气。若短时间(1-2小时)内病情无改善甚至恶化，应当及时进行气管插管和有创机械通气。
(3)有创机械通气：采用肺保护性通气策略，即小潮气量(4-8ml/kg理想体重)和低吸气压力(平台压＜30cmH 2O)进行机械通气，以减少呼吸机相关肺损伤。较多患者存在人机不同步，应当及时使用镇静以及肌松剂。
(4)挽救治疗：对于严重急性呼吸窘迫综合征(ARDS)患者，建议进行肺复张。在人力资源充足的情况下，每天应当进行12小时以上的俯卧位通气。俯卧位通气效果不佳者，如条件允许，应当尽快考虑体外膜肺氧合(ECMO)。
3.循环支持：充分液体复苏的基础上，改善微循环，使用血管活性药物，必要时进行血流动力学监测。
4.其他治疗措施
可根据患者呼吸困难程度、胸部影像学进展情况，酌情短期内(3～5曰)使用糖皮质激素，建议剂量不超过相当于甲泼尼龙1-2mg/kg/日，应当注意较大剂量糖皮质激素由于免疫抑制作用，会延缓对冠状病毒的清除； 可静脉给予血必净100ml/次，每日2次治疗；可使用肠道微生态调节剂，维持肠道微生态平衡，预防继发细菌感染；可采用恢复期血浆治疗；对有高炎症反应的危重患者，有条件可以考虑使用体外血液净化技术。
在本发明的具体实施方案中，“中医治疗”一般包括以下方案：
1.医学观察期
临床表现1：乏力伴胃肠不适
推荐中成药：藿香正气胶囊(丸、水、口服液)
临床表现2：乏力伴发热
推荐中成药：金花清感颗粒、连花清瘟胶囊(颗粒)、疏风解毒胶囊(颗粒)、防风通圣丸(颗粒)
2.临床治疗期
(1)初期：寒湿郁肺
临床表现：恶寒发热或无热，干咳，咽干，倦怠乏力，胸闷，脘痞，或呕恶，便溏。舌质淡或淡红，苔白腻，脉濡。
推荐处方：苍术15g、陈皮10g、厚朴10g、藿香10g、草果6g、生麻黄6g、羌活10g、生姜10g、槟郎10g
(2)中期：疫毒闭肺
临床表现：身热不退或往来寒热，咳漱痰少，或有黄痰，腹胀便秘。胸闷气促，咳嗽喘憋，动则气喘。舌质红，苔黄腻或黄燥，脉滑数。
推荐处方：杏仁10g、生石膏30g、瓜萎30g、生大黄6g(后下)、生炙麻黄各6g、葶苈子10g、桃仁10g、草果6g、槟郎10g、苍术10g
推荐中成药：喜炎平注射剂，血必净注射剂
(3)重症期：内闭外脱
临床表现：呼吸困难、动辄气喘或需要辅助通气，伴神昏，烦躁，汗出肢冷，舌质紫暗，苔厚腻或燥，脉浮大无根。
推荐处方：人参15g、黑顺片10g(先煎)、山茱萸15g，送服苏合香丸或安宫牛黄丸
推荐中成药：血必净注射液、参附注射液、生脉注射液
(4)恢复期：肺脾气虚
临床表现：气短、倦怠乏力、纳差呕恶、痞满，大便无力，便溏不爽，舌淡胖，苔白腻。
推荐处方：法半夏9g、陈皮10g、党参15g、炙黄芪30g、茯苓15g、藿香10g、砂仁6g。
实施例1受试者CD4 +T细胞中GM-CSF、IFN-γ和IL-6的表达
利用流式细胞术对33例新型冠状病毒肺炎病人(含12例ICU重型病人，21例普通型病人)和10例正常人外周血免疫细胞的比例、绝对数和表型分子进行检测。
检测了干扰素-γ(IFNγ)、集落刺激因子(GM-CSF)和IL-6这些炎性风暴的主要因子，结果发现，相比于对照组正常人，在新型冠状病毒肺炎患者中，新鲜的CD4 +T细胞仍然产生高比例GM-CSF、IFN-γ和IL-6，ICU重型患者表达水平更高(见图1)。
实施例2受试者单核细胞中IL-6的表达情况
利用流式细胞术对上述33例新型冠状病毒肺炎病人(含12例ICU重型病人，21例普通型病人)和10例正常人外周血免疫细胞的比例、绝对数和表型分子进行检测。
其中，单核细胞是外周免疫细胞的重要组成部分，通过流式内标细胞因子方法，检测了细胞因子风暴的主要因子IL-6。与对照组正常人相比，发现在新型冠状病毒肺炎患者中，CD4 +Monocytes(单核细胞)产生高比例的IL-6，重要的是，在ICU重型患者中，这些炎症性单核细胞还分泌高水平IL-6，加剧细胞因子风暴(见图2)。以上说明了IL-6是关键的免疫治疗靶点。
实施例3施用托珠单抗后，受试者的生化指标变化
临床上用于风湿性疾病的药物“托珠单抗”注射液可以阻断白介素6通路。根据国家“关于印发新型冠状病毒肺炎诊疗方案(试行第五版修正版)的通知”国卫办医函(2020)117号文件，对中国科学技术大学附属第一院和安徽省阜阳第二人民院共6例患者进行了临床分型，其中普通型1例， 重型5例，并采用“托珠单抗+常规治疗”的新治疗方案；其中，常规治疗为根据国家“关于印发新型冠状病毒肺炎诊疗方案(试行第五版修正版)的通知”国卫办医函(2020)117号所定义的常规治疗。
本实施例中的6例患者已经经历了4-10天的常规治疗，7例患者双肺依然典型病变，且6例都表现出高热(平均发热时间为7.8天，平均体温达到38.3℃)，6例当中有2例白细胞低于正常参考区间(参考区间为3.5-9.5，单位为×10 9/L)，6例全部淋巴细胞计数低于正常参考区间(参考区间为1.1-3.2，单位为×10 9/L)，6例全部血清白细胞介素6(IL-6)水平高于正常参考区间(参考区间为＜7，单位pg/ml)，6例全部血清C反应蛋白水平高于正常参考区间(参考区间为＜8，单位mg/l)，6例全部氧合指数低于正常参考区间(参考区间400-500，单位mmhg)如表1所示。
经过托珠单抗静脉输注400mg治疗，24小时以后，6例发热病人体温降至正常(体温低于或等于37℃)，并且体温84小时维持正常。其中体温变化通过统计学分析(配对T检验)，差异显著，如图3所示。其中病例7用药前后的CT影像见图4，从图中可见，患者的肺部炎症得到了显著改善。
另外，在用药24小时后，6例受试者的血项指标变化如表1所示。其中5例患者白细胞和/或淋巴细胞数量上升，说明了机体免疫功能在恢复，抗病毒能力在提高；6例患者C反应蛋白下降，说明了机体的炎症反应下降，细胞因子风暴降低；同时，5例患者氧合指数较前改善(参见表1)。IL6是细胞因子，需通过其受体(IL6受体)才能发挥效应功能。托珠单抗是针对IL6受体，阻断IL6与其受体结合，达到阻断IL6功能的作用。托珠单抗治疗后，IL6无法与其受体结合，IL6就会消耗不掉，在机体积累，故治疗后血液IL6水平会升高；但即使升高，这时候机体有托珠单抗的存在，它也不能发挥效应功能。
Figure PCTCN2020082994-appb-000001
实施例4：托珠单抗治疗新冠肺炎患者
总共有21例患者参与了托珠单抗治疗。其中7例患者在中国科技大学第一附属医院(安徽省立医院)接受治疗，14例患者在安徽阜阳第二人民医院接受治疗。所有登记的患者都符合中华人民共和国国家卫生健康委员会发起的《新型冠状病毒肺炎诊疗方案》(试行第6版)(Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia，6 th interim edition，China NHCOTPSRO)中所定义的重型或危重型标准。即在确诊为新冠肺炎患者的基础上，如果满足以下条件中的任何一个，则定义重型诊断：(1)呼吸速率≥30次/分钟；(2)呼吸室内空气时SpO2≤93％；(3)PaO2/FiO2≤300mmHg。如果有以下任何一种情况，则诊断为危重型病例：(1)需要机械通气的呼吸衰竭；(2)休克；(3)合并其它器官功能衰竭，需要进入ICU。
安徽省立医院的医学研究伦理委员会批准了该研究。所有患者在使用托珠单抗之前均已签署知情同意书，并同意公布该病例系列。我们致力于保护患者隐私并遵守赫尔辛基宣言。
(审批号：2020-XG(H)-015)
IL-6测试
通过电化学发光法(Roche Diagnostics GmbH)或FACS分析来测量IL-6的值。在不添加任何再刺激的情况下，进行IL-6的细胞内染色。然后根据eBioscience的说明书，收集、洗涤和封闭细胞。IL-6的正常范围小于7pg/ml。
治疗与观察
所有患者均根据《新型冠状病毒性肺炎诊疗方案》(试行第六版)接受标准护理，包括洛匹那韦、甲泼尼龙，其他症状缓解剂和氧疗，并加用托珠单抗(Roche Pharma(Schweiz)Ltd，B2084B21)，通过静脉滴注一次400mg。记录包括体温、氧饱和度等在内的临床特征。重复进行全血白细胞计数。在入院时和在开始托珠单抗治疗后一周，对所有患者均进行了螺旋计算机断层扫描(CT)，其在全肺、低剂量暴露中使用64排螺旋Optima CT680扫描仪(美国GE Healthcare)，用5毫米切片扫描。
数据采集
通过图表和图形回顾收集治疗数据，包括性别、年龄、共存疾病、临床症状、外周氧饱和度。该研究关注于使用托珠单抗治疗之前和之后的体温、呼吸功能和CT结果的变化。
统计分析
所有统计数据均通过IBM SPSS软件16.0版(Chicago，IL，USA)进行分析，并表示为平均值±标准差。
结果
人口统计特征
受试者的平均年龄为56.8±16.5岁，范围为25至88岁(表2)。在21例患者中，18位男性(85.7％)和3位女性(14.3％)。17例患者(81.0％)被评估为重型和4例患者(19.0％)被评估为危重型。其中，5例患者(23.8％)具有暴露病史，6例患者(28.6％)具有暴露于已确诊COVID-19的患者。18例患者(85.7％)接受了一次托珠单抗治疗，3例患者(14.3％)由于在12小时内发热而接受了再次相同剂量的托住单抗治疗。
临床表现(presentation)
所有患者都表现出发热作为第一症状，随后是于咳(14/21，66.7％)、少量白痰(9/21，42.9％)、乏力(6/21，28.6％)和呼吸困难(6/21，28.6％)。4例患者(19.0％)有恶心。其它症状包括流涕和胸痛是罕见的(4.8％)。在所有患者中，从发热发作到呼吸困难发生存在着6天的中位间隔(范围为2-14天)。20例患者需要氧疗，包括9例患者(45.0％)需要高流量氧疗、7例患者(35.0％)需要鼻导管、1例患者(5.0％)需要面罩通氧、1例患者(5.0％)无创通气和2例患者(10.0％)有创通气。(表2)
实验室检查
白细胞计数显示，4例患者(4/20，20.0％)在外周血中有异常值(平均为6.30±2.77x 10 9/L)。(表3)。85.0％患者的淋巴细胞百分比降低(17/20，平均为15.52±8.89％)。所有20例患者的C-反应蛋白(CRP)水平均增加(平均为75.06±66.80mg/L)。中位降钙素原(PCT)值为0.33±0.78ng/mL，20例患者中仅有2名(10.0％)呈现异常值。此外，在托珠单抗治疗之前，对所有患者进行了IL-6表达水平的分析，平均为132.38±278.54pg/ml，显示在这些重型和危重型COVID-19患者中IL-6上调。
成像特征
[根据细则91更正 22.06.2020]　
所有患者均表现出异常胸部CT。最初胸部CT的主要异常是斑块状、磨玻璃影(ground-glass opacities)和局灶性肺实变(focal consolidation)，主要分布在外周，尤其是胸膜下区域(图5A-C)。在入院后的最初7天内，21例患者的磨玻璃影的大小、程度和严重性增加。未发现胸膜积液、纵隔结或中央肺栓塞。
治疗结果
在接受托珠单抗之后，所有患者的体温在第一天显著恢复正常，然后保持稳定(图6B)。在随后的几天中，临床症状同时显著减轻。外周氧饱和度显著改善(图6C-D)。1例患者不需要进一步的氧疗。15例患者(15/20，75.0％)已经降低了他们的氧摄入。在托珠单抗治疗后的第一天，1例患者撤下了呼吸机。1例危重型患者在第五天进行气管拔管并恢复意识。另一位先前已接受有创通气的患者降低了呼吸机的参数，并且预期不久将关闭呼吸机。
如表3，表5-8和图6A所示，在接受托珠单抗治疗后，淋巴细胞百分比和CRP水平发生了显著变化。在治疗后的第五天，仅2例患者(2/19，10.5％)具有白细胞计数异常值，平均为5.25±2.11x10 9/L。10例患者(10/19，52.60％)的淋巴细胞百分比恢复正常(平均为22.62±13.48％)。治疗后第5天，84.20％患者的CRP显著降低并恢复正常(16/19，平均为2.72±3.60mg/L)。治疗后，CT扫描显示19例患者(90.5％)吸收了病灶，其他患者有少许改善(用药前后CT扫描见图5A-C和图5D-F)。19例患者(90.5％)已经出院，其中包括2位危重型患者，其余患者仍在医院观察中，但是他们的体温保持正常(表4)，所有症状均得到显著改善。托珠单抗治疗后，平均住院时间为13.5±3.1天。(表2)。没有随后发生肺部感染和疾病恶化或死亡的报道。在用托利珠单抗治疗期间，没有药物不良反应的报道。
讨论
在这项研究中，所有21例患者在接受妥珠单抗治疗之前均具有一周的常规治疗史，但是随着持续发热、低氧血症和CT图像恶化而恶化。在用托珠单抗治疗后，除了改善体温之外(见表4)，大多数患者的呼吸功能均有一定程度的改善。胸闷得到缓解。15例患者(75.0％)降低了氧气摄入 流量，并且氧饱和度保持稳定。在用托珠单抗治疗后的5天内，有2例患者撤下了呼吸机，并且另1例危重型患者有望在短时间内撤下呼吸机。
已认为淋巴细胞百分比的降低是在COVID-19患者中诊断和严重性判断的重要指标(Wang D，Hu C et al.，Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan，China，JAMA 2020.DOI：10.1001/JAMA.2020 1585)。在我们的研究中发现，在给予托珠单抗5天内，85.0％的患者(17/20)中淋巴细胞百分比降低，并且52.6％的患者(10/19)中淋巴细胞百分比恢复正常。同时，升高的CRP也恢复正常。在19例患者(90.5％)中，CT扫描的肺部磨玻璃影被吸收。考虑到肺组织损伤需要足够的时间进行修复，因此可以预期CT扫描中的缓解延迟。在治疗期间，没有药物不良反应和随后的肺部感染的报道。所有患者的临床症状均有显著改善，治疗后预后良好。19例患者(90.5％)已经出院，其中包括2位危重型患者。因此，托珠单抗可有效治疗重型COVID-19患者，这可能是由于与IL-6相关的发热和炎性风暴应答的阻断。
表2：患者的人口统计学特征
Figure PCTCN2020082994-appb-000002
[根据细则26改正01.07.2020]　
Figure WO-DOC-FIGURE-0709
Figure PCTCN2020082994-appb-000004
CHD，冠心病；COPD，慢性阻塞性肺病；CKD，慢性肾病。除非另有说明，否则数据为n/N(％)。
*加-减值为平均±SD。
**已确诊为COVID-19的患者。
***托珠单抗治疗后的住院数天。
表3：托珠单抗治疗之前和之后的实验室检测
Figure PCTCN2020082994-appb-000005
Figure PCTCN2020082994-appb-000006
注：数据为平均±SD(异常数/总数，％)。因临床特殊情况，一些数据未能及时收集
表4：托珠单抗治疗前后患者的体温(℃)表
Figure PCTCN2020082994-appb-000007
表5：托珠单抗治疗前后IL-6水平
Figure PCTCN2020082994-appb-000008
Figure PCTCN2020082994-appb-000009
注：因疫情特殊情况，一些数据未能及时收集
表6：托珠单抗治疗前后C反应蛋白水平
Figure PCTCN2020082994-appb-000010
Figure PCTCN2020082994-appb-000011
注：因疫情特殊情况，一些数据未能及时收集
表7：托珠单抗治疗前后淋巴细胞计数
Figure PCTCN2020082994-appb-000012
注：因疫情特殊情况，一些数据未能及时收集
表8：托珠单抗治疗前后白细胞计数
Figure PCTCN2020082994-appb-000013
Figure PCTCN2020082994-appb-000014
以上结果表明，IL-6受体抗体托珠单抗，特别是400mg的托珠单抗，实现下述一种或多种效果：C反应蛋白明显下降；发热反应明显降低，体温降至正常；免疫细胞数量增加，具体体现为外周白细胞和淋巴细胞数量明显回升，其有利于抗病毒反应；肺脏损伤减少，具体体现为氧合指数得到改善，对于治疗新型冠状病毒肺炎具有良好效果。
以上所述的具体实施例，对本发明的目的、技术方案和有益效果进行了进一步详细说明，应理解的是，以上所述仅为本发明的具体实施例而已，并不用于限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (13)

  1. IL-6受体抗体，优选托珠单抗(优选350mg-450mg，更优选单次药物剂量单元为350-450mg的托珠单抗)在制备用于治疗患有新型冠状病毒肺炎的患者的药物或试剂盒中的用途，优选地，所述患者为轻型患者，普通型患者，重型患者或危重型患者。
  2. 权利要求1所述的用途，其中所述药物或试剂盒进一步包含抗病毒制剂和任选地中药制剂，其中当所述IL-6受体抗体存在于试剂盒中时，所述IL-6受体抗体与抗病毒制剂和任选地所述中药制剂同时、依次或分别施用，其中所述中药制剂包括但不限于喜炎平注射剂、血必净注射剂、参附注射液和/或生脉注射液。
  3. 根据权利要求2所述的用途，其中，所述抗病毒制剂为α-干扰素(优选单次药物剂量单元为500万U的α-干扰素)、洛匹那韦/利托那韦(优选单次药物剂量单元为200mg的洛匹那韦，单次药用剂量单元的利托那韦为50mg)或利巴韦林(优选单次药物剂量单元为500mg的利巴韦林)；其中
    优选地，所述α-干扰素的单次施用剂量为500万U剂量，每日2次；所述洛匹那韦/利托那韦的单次施用剂量分别为200mg/50mg每粒，每日2次；所述利巴韦林的单次施用剂量为500mg/次，每日2-3次。
  4. 根据前述任一项权利要求所述的用途，其中，所述IL-6受体抗体为托珠单抗。
  5. 根据权利要求4所述的用途，其中，所述托珠单抗的单次施用剂量为350mg，360mg，370mg，380mg，390mg，400mg，410mg，420mg，430mg，440mg或450mg，更优选400mg；优选地，所述托珠单抗为适于静脉输注的形式。
  6. 一种药物组合物或单次药物剂量单元(优选用于治疗新型冠状病毒肺炎的患者)，其含有IL-6受体抗体(优选350-450mg，更优选为350mg，360mg，370mg，380mg，390mg，400mg，410mg，420mg，430mg，440mg 或450mg，进一步优选400mg)，优选地，所述患者为轻型患者，普通型患者，重型患者或危重型患者。
  7. 根据权利要求6所述的药物组合物或单次药物剂量单元，其还包含抗病毒制剂，以及任选地糖皮质激素。
  8. 根据权利要求7所述的药物组合物或单次药物剂量单元，其中，所述抗病毒制剂为α-干扰素、洛匹那韦/利托那韦或利巴韦林。
  9. 根据权利要求6-8任一项所述的药物组合物或单次药物剂量单元，其中，所述IL-6受体抗体为托珠单抗。
  10. 根据权利要求6所述的药物组合物或单次药物剂量单元，其还与中药制剂联用，其中所述中药制剂包括但不限于喜炎平注射剂、血必净注射剂、参附注射液和/或生脉注射液。
  11. 包含IL-6受体抗体的静脉施用器械的制品，其向新型冠状病毒肺炎的患者施用固定剂量的IL-6受体抗体(优选托珠单抗)，所述固定剂量为350-450mg，优选为350mg，360mg，370mg，380mg，390mg，400mg，410mg，420mg，430mg，440mg或450mg，更优选400mg。
  12. 治疗新型冠状病毒肺炎的患者的方法，其特征在于给予所述患者350mg-450mg的托珠单抗，优选400mg托珠单抗。
  13. 权利要求12所述的治疗新型冠状病毒肺炎的患者的方法，其中所述托珠单抗与抗病毒药物(如α-干扰素、洛匹那韦/利托那韦或利巴韦林)和/或抗炎药(如甲泼尼龙)和/或中药制剂联合使用，其中所述中药制剂包括但不限于喜炎平注射剂、血必净注射剂、参附注射液和/或生脉注射液。
PCT/CN2020/082994 2020-02-19 2020-04-02 Il-6受体抗体的新用途 WO2021164107A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010103449.6 2020-02-19
CN202010103449 2020-02-19

Publications (1)

Publication Number Publication Date
WO2021164107A1 true WO2021164107A1 (zh) 2021-08-26

Family

ID=72180041

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/082994 WO2021164107A1 (zh) 2020-02-19 2020-04-02 Il-6受体抗体的新用途

Country Status (2)

Country Link
CN (1) CN111588850A (zh)
WO (1) WO2021164107A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021206637A1 (en) * 2020-04-07 2021-10-14 Agency For Science, Technology And Research A method of assessing a disease state in a subject infected with coronavirus
CN112007138B (zh) * 2020-09-25 2022-01-28 漯河市第一人民医院 一种治疗湿毒闭肺型病毒性肺炎的柴黄姜术中药合剂

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1541713A (zh) * 2003-11-06 2004-11-03 娟 孙 杂交疫苗载体及其应用
CN1849135A (zh) * 2003-04-28 2006-10-18 中外制药株式会社 治疗白介素－6相关疾病的方法
WO2012071554A2 (en) * 2010-11-23 2012-05-31 Alder Biopharmaceuticals, Inc. Anti-il-6 antibodies for the treatment of oral mucositis
WO2017202387A1 (en) * 2016-05-27 2017-11-30 Beijing Vdjbio Co., Ltd. Antibodies, composition and kits comprising same, and methods of use thereof
CN110337445A (zh) * 2016-12-23 2019-10-15 印度血清研究所私人有限公司 用于提高哺乳动物细胞培养物中的抗体生产力并最小化下游、配制过程中的聚集的改进的方法，以及由其获得的稳定抗体制剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1849135A (zh) * 2003-04-28 2006-10-18 中外制药株式会社 治疗白介素－6相关疾病的方法
CN1541713A (zh) * 2003-11-06 2004-11-03 娟 孙 杂交疫苗载体及其应用
WO2012071554A2 (en) * 2010-11-23 2012-05-31 Alder Biopharmaceuticals, Inc. Anti-il-6 antibodies for the treatment of oral mucositis
WO2017202387A1 (en) * 2016-05-27 2017-11-30 Beijing Vdjbio Co., Ltd. Antibodies, composition and kits comprising same, and methods of use thereof
CN110337445A (zh) * 2016-12-23 2019-10-15 印度血清研究所私人有限公司 用于提高哺乳动物细胞培养物中的抗体生产力并最小化下游、配制过程中的聚集的改进的方法，以及由其获得的稳定抗体制剂

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GUPTA PARAKRITI, GOYAL KAPIL, KANTA POONAM, GHOSH ARNAB, SINGH MINI P.: "Novel 2019-Coronavirus on New Year’s Eve", INDIAN JOURNAL OF MEDICAL MICROBIOLOGY, vol. 37, no. 4, 31 December 2019 (2019-12-31), pages 459 - 477, XP055773157, ISSN: 0255-0857, DOI: 10.4103/ijmm.IJMM_20_54 *

Also Published As

Publication number Publication date
CN111588850A (zh) 2020-08-28

Similar Documents

Publication Publication Date Title
National Health Commission & National Administration of Traditional Chinese Medicine Diagnosis and treatment protocol for novel coronavirus pneumonia (Trial Version 7)
Jin et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)
Jin et al. Chemoprophylaxis, diagnosis, treatments, and discharge management of COVID-19: an evidence-based clinical practice guideline (updated version)
Zhou et al. Traditional Chinese medicine shenhuang granule in patients with severe/critical COVID-19: a randomized controlled multicenter trial
Widness et al. Changing patterns of red blood cell transfusion in very low birth weight infants
WO2021155777A1 (zh) 药物组合物在预防和治疗新型冠状病毒肺炎中的应用
García-Salido et al. Spanish consensus document on diagnosis, stabilisation and treatment of pediatric multisystem inflammatory syndrome related to SARS-CoV-2 (SIM-PedS)
Furukawa et al. The effectiveness of dapagliflozin for sleep-disordered breathing among Japanese patients with obesity and type 2 diabetes mellitus
WO2021164107A1 (zh) Il-6受体抗体的新用途
Bao et al. Clinical features of COVID-19 in a young man with massive cerebral hemorrhage—case report
BEAUDRY et al. Severe allergic pneumonitis from hydrochlorothiazide
He Translation: Diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7): National Health Commission, National Administration of Traditional Chinese Medicine
Gharehbaghi et al. COVID-19 in children and neonates: a comprehensive review article
Blair Remdesivir: a review in COVID-19
Zielecki et al. Effective treatment of severe acute pancreatitis and COVID-19 pneumonia with tocilizumab
Xu et al. Translation: management of Coronavirus disease 2019 (COVID-19): experience in Zhejiang Province, China
General Office of National Health CommissionOffice et al. Diagnosis and treatment protocol for COVID-19 patients (tentative 8th edition)
Carmona et al. The Covid-19 pandemic seen from the frontline
Released by National Health Commission of People's Republic of China & National Administration of Traditional Chinese Medicine on January 5, 2023 Diagnosis and treatment protocol for COVID‐19 patients (Tentative 10th Version)
Fukunaga et al. A remarkable elevation in the procalcitonin levels due to diabetic ketoacidosis in a hemodialysis patient
Sobhy et al. Early use of ibuprofen in moderate cases of COVID-19 might be a promising agent to attenuate the severity of disease: a randomized controlled trial
Song et al. Protease inhibitor use in COVID-19
National Health Commission Translation: diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7)
Ba-Shammakh et al. Clinical Dilemmas in Immune Thrombocytopenic Purpura With Diffuse Alveolar Hemorrhage: Diagnosis, Treatment, and Outcomes
Mostafavi et al. Successful recovery of a child with COVID-19-induced secondary hemophagocytic lymphohistiocytosis

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: 20920364

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20920364

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1)N EPC