CN116490520A - Tozumaab and adefovir combination therapy for covd-19 pneumonia - Google Patents

Tozumaab and adefovir combination therapy for covd-19 pneumonia Download PDF

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CN116490520A
CN116490520A CN202180023252.4A CN202180023252A CN116490520A CN 116490520 A CN116490520 A CN 116490520A CN 202180023252 A CN202180023252 A CN 202180023252A CN 116490520 A CN116490520 A CN 116490520A
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pneumonia
antibody
patient
dose
ser
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包敏
L·W·蔡
M·D·艾斯纳
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Genentech Inc
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Genentech Inc
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Priority claimed from PCT/US2021/023061 external-priority patent/WO2021194860A1/en
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Abstract

The present application describes a method of treating viral pneumonia in a patient, said method comprising administering to said patient an effective amount of a combination of tolizumab and adefovir.

Description

Tozumaab and adefovir combination therapy for covd-19 pneumonia
Statement regarding federally sponsored research or development
The present invention was completed with government support under contract number HHSO100201800036C awarded by the biomedical advanced research and development agency of the U.S. health and public service. The government has certain rights in this invention.
Cross Reference to Related Applications
The present application claims the benefit of U.S. provisional application number 62/993589 filed 3/23 in 2020 and U.S. provisional application number 63/011,889 filed 4/17 in 2020, which provisional applications are incorporated herein by reference in their entirety.
Sequence listing
The present application contains a sequence listing submitted through the ffs-web and incorporated herein by reference in its entirety. The ASCII copy was created at 2021, 3, 15, and named p 363831 woseqlist. Txt, 7,358 bytes in size.
Technical Field
The present invention relates to methods of treating pneumonia in a patient with an IL6 antagonist. It includes methods of treating viral pneumonia, such as coronavirus pneumonia, and is exemplified by covd-19 pneumonia. In one embodiment, it involves administering to a patient a weight-based intravenous dose of tolizumab, wherein the weight-based dose is 8mg/kg of tolizumab. In one embodiment, no increase in IL-6 levels in the patient is found. Optionally, the method further comprises administering to the patient a second weight-based 8mg/kg intravenous dose of tolizumab 8-12 hours after the first dose (e.g., 8-11 hours after the first dose) or 8-24 hours after the first dose, wherein after the first dose the patient does not experience improvement or ≡a category of exacerbation on an ordered scale of clinical status. In another embodiment, it relates to administering an IL6 antagonist (e.g., an IL6 receptor antibody, such as tolizumab) to a patient in an amount effective to achieve a greater improvement in clinical outcome than standard of care (SOC), e.g., as measured on an ordered list of clinical states, optionally in combination with other efficacy and safety outcomes disclosed in more detail herein. In another embodiment, the invention relates to a method of treating Acute Respiratory Distress Syndrome (ARDS) in a patient without elevated IL6 levels comprising administering an IL6 antagonist (e.g., an IL6 receptor antibody, such as tolizumab) to the patient.
Background
Interleukin 6 (IL-6) is a pro-inflammatory multifunctional cytokine produced by a variety of cell types. IL-6 is involved in a variety of processes such as T cell activation, B cell differentiation, induction of acute phase proteins, stimulation of hematopoietic precursor cell growth and differentiation, promotion of osteoclast differentiation from precursor cells, proliferation of liver cells, dermis cells and nerve cells, bone metabolism and lipid metabolism (Hirano T. Chem immunol.51:153-180 (1992); keller et al front biosci.1:340-357 (1996); metzger et al Am J Physiol Endocrinol Metab.281:E597-E965 (2001); tamura et al Proc Natl Acad Sci USA.90:11924-11928 (1993); taub R.J Clin Invest112:978-980 (2003)). IL-6 has been implicated in the pathogenesis of a variety of diseases, including autoimmune diseases, osteoporosis, neoplasia and aging (Hirano, T. (1992), supra; and Keller et al, supra). IL-6 exerts its effect through ligand-specific receptors (IL-6R) both in soluble form and in membrane-expressed form.
IL-6 levels in serum and synovial fluid of Rheumatoid Arthritis (RA) patients were reported to be elevated, indicating synovial membrane production of IL-6 (Irano et al Eur J Immunol.18:1797-1801 (1988); and Houssiau et al Arthritis Rheum.1988;31:784-788 (1988)). IL-6 levels are associated with disease activity in RA (Hirano et al (1988), supra), whereas clinical efficacy is accompanied by a decrease in serum IL-6 levels (Madhok et al Arthritis Rheum.33:S154. Act (1990)).
Torpedo mab (TCZ) is a recombinant humanized monoclonal antibody of the immunoglobulin IgG1 subclass that binds to the human IL-6 receptor. Roche and Chugai have completed or are undergoing clinical efficacy and safety studies of intravenous injection (iv) of TCZ in a number of disease areas, including adult-onset RA, systemic juvenile idiopathic arthritis (sJIA) and polyarthritis juvenile idiopathic arthritis (pJIA).
Tolizumab is approved in the united states for use:
1. adult patients with moderate to severe active Rheumatoid Arthritis (RA) who are under-responsive to one or more disease-modifying antirheumatic drugs (DMARDs).
2. Giant Cell Arteritis (GCA): adult patients with giant cell arteritis.
3. Polyarthritis juvenile idiopathic arthritis (pJIA): patients 2 years old and older with active polyarthritis juvenile idiopathic arthritis.
4. Systemic juvenile idiopathic arthritis (sJIA): patients aged 2 and older with active systemic juvenile idiopathic arthritis.
5. Cytokine Release Syndrome (CRS): adult and child patients 2 years and older who have a Chimeric Antigen Receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome.
Coronaviruses (covs) are positive strand RNA viruses that appear coronally under electron microscopy due to the presence of spike glycoproteins on the envelope. They are a large class of viruses that can cause diseases ranging from common cold to more severe, such as middle east respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV).
Covd-19 is an acronym for "2019 coronavirus disease" and is caused by a new strain of coronavirus that has not been previously found in humans and has been newly named by the World Health Organization (WHO) on month 2 and 11 of 2020.
By 17 days of 3 months in 2020, more than 100 countries worldwide report more than 179,000 cases of covd-19, more than 7400 deaths, according to the world health organization. Up to about 20% of infected patients develop complications associated with severe forms of interstitial pneumonia, which may progress to Acute Respiratory Distress Syndrome (ARDS) and/or Multiple Organ Failure (MOF) and death.
To date, no vaccine or specific antiviral drug has proven effective in preventing or treating covd-19. Most patients with mild disease recover after symptomatic and supportive care. However, those with a heavier condition require hospitalization (WHO 2020).
CRS has been identified as a clinically significant, on-target, tumor-shedding side effect of CAR T cell therapy for the treatment of malignancy. Features of CRS include fever, fatigue, headache, encephalopathy, hypotension, tachycardia, coagulation disorders, nausea, capillary leakage and multiple organ dysfunction. CRS incidence reported after CAR T cell therapy varies from 50% to 100%, with 13% to 48% of patients experiencing severe or life threatening forms. Serum levels of inflammatory cytokines are elevated, especially interleukin 6 (IL-6). The severity of the symptoms may be related to serum cytokine concentration and duration of exposure to inflammatory cytokines.
Tozumazumab was approved by the U.S. food and drug administration at 8 and 30, 2017A severe or life threatening CAR T cell-induced CRS for use in the treatment of adult and child patients 2 years old and older. Approved dosage is 8mg/kg of body weight 30kg or more and 12mg/kg of body weight 30kg <. If the sign/symptom is not improved, a maximum of three additional doses may be administered, and the interval between subsequent doses should be at least 8 hours.
The approval of TCZ was based on the use of temsiren in prospective clinical trialsOr AlkylrensaiRetrospective analysis of data for patients who developed CRS after treatment and were treated with TCZ (Le et al, the oncology t.23:943-947 (2018)). 31 of the 45 patients from CTL019 series (69%) reached a response at 14 days of the first dose of TCZ (defined as no fever and no vasopressors for at least 24 hours and no other treatments than corticosteroids for 14 days of the first dose of TCZ (up to two doses)) and the median time from the first dose to the response was 4 days. 8 of the 15 patients from the alemtuquor series (53%) achieved remission and the median time to remission was 4.5 days. The response rates among subgroups, such as age group, gender, race, ethnicity, CRS rank at first TCZ dose, CRS duration before TCZ treatment, etc., were substantially uniform. There is no report on adverse reactions caused by TCZ.
Pharmacokinetic (PK) data were available for 27 patients after the first dose of TCZ and 8 patients after the second dose of TCZ. Based on 131 PK observations, the geometric mean (% CV) maximum concentration of TCZ in CAR T cell-induced severe or life-threatening CRS patients was 99.5 μg/mL (36.8%) after the first infusion and 160.7 μg/mL (113.8%) after the second infusion. PK model analysis showed that patients with CRS had faster TCZ clearance than healthy volunteers and other patient populations, and simulations showed that exposure of patients with CRS up to four doses of TCZ at least 8 hours apart was considered acceptable.
TCZ is also approved in the european union and in certain other countries for CAR-T induced severe or life threatening CRAs.
Chinese doctors began using TCZ outside of the label for the treatment of coronavirus (covd-19) pneumonia. Based on the results of the observational study on 21 TCZ-treated covd-19 patients, a randomized open-label study initiated by the investigator (n=188) was also initiated on 13 days 2 and 2020.
TCZ was listed by the national health committee of china, 3 months and 3 days, as a treatment option for severe or critical forms of covd-19 pneumonia, by the seventh edition of covd-19 pneumonia diagnosis and treatment. Chinese CDC defines disease severity according to the following criteria:
1. Severe pneumonia: dyspnea, respiratory rate not less than 30/min, and blood oxygen saturation (SpO) 2 )≤93％，PaO2/FiO 2 Ratio [ blood pressure of oxygen (partial pressure of oxygen, paO 2) and percent oxygen supply (fraction of oxygen inhaled, fiO) 2 ) Ratio of]< 300mmHg, and/or lung infiltration > 50% over 24 to 48 hours; this occurs in 14% of cases.
2. Severe pneumonia: respiratory failure, septic shock and/or Multiple Organ Dysfunction (MOD) or failure (MOF); this occurs in 5% of cases (Wu et al jama. Doi:10.1001/jama.2020.2648 (2020)).
According to section 10.3.7 of these guidelines: "Tozumazumab therapy may be attempted for patients with extensive lesions and severe lung, as well as for patients whose laboratory tests have elevated IL-6 levels. The first dose is 4 to 8mg/kg, the recommended dose is 400mg,0.9% saline is diluted to 100ml, and infusion time is over 1 hour; if there is no clinical improvement in symptoms and signs after the first dose, it can be applied more than 12 hours later at the same dose as before. The number of cumulative administrations is up to 2 and the single maximum dose does not exceed 800mg. Note that allergic constitution, tuberculosis and other active infections are forbidden. "
Based on the results of the first 21 patients retrospectively observed study in which patients with severe or critical coronavirus (covd-19) pneumonia received TCZ treatment, a randomized control trial (n=188) had been initiated in the same population to test the same TCZ dosage regimen, which was currently ongoing, recruiting about 70 patients. Xu et al Effective treatment of severe COVID-19patients with tocilizumab submitted manuscripts [ resources on the internet ].2020[ updated 3/5/2020; 3 months, 17 days 2020 ]. Available from http:// www.chinaxiv.org/abs/202003.00026.
Twenty-one patients with severe or critical grade covd-19 pneumonia were treated with TCZ IV (400 mg) plus standard care in february 2020. The average age of the patients was 56.8+ -16.5 years, ranging from 25 to 88 years. 17 patients (81.0%) were evaluated as severe, and 4 (19.0%) were evaluated as critical. Lymphopenia occurred in most patients (85%). The levels of C-reactive protein (CRP) were elevated (average, 75.06.+ -. 66.80 mg/L) in all 20 patients. The median Procalcitonin (PCT) value was 0.33.+ -. 0.78ng/mL and the average IL-6 level before the occurrence of abnormal TCZ was 132.38.+ -. 278.54pg/mL (normal <7 pg/mL) for only 2 out of 20 patients (10.0%).
The standard care consisted of lopinavir, methylprednisolone, other symptomatic relief agents and oxygen therapy as recommended by the new coronavirus pneumonia treatment protocol (sixth edition). All 21 patients had received conventional standard of care treatment for one week before sustained fever, hypoxia and chest CT image deterioration.
18 patients (85.7%) received one TCZ and 3 patients (14.3%) received a second dose due to fever within 12 hours. According to the authors, fever returns to normal after TCZ treatment and other symptoms are markedly improved. 15 of the 20 patients (75.0%) reduced their oxygen intake and one patient did not require oxygen therapy. CT scans showed significant relief of double lung turbidity in 19/20 patients (90.5%) after TCZ treatment. The percentage of lymphocytes in peripheral blood was reduced in 85.0% (17/20) of patients before treatment (average, 15.52.+ -. 8.89%) and recovered to normal in 52.6% (10/19) of patients on the fifth day after treatment. Abnormally elevated CRP was significantly reduced in 84.2% (16/19) patients. Adverse drug reactions and subsequent pulmonary infections were not reported.
19 patients (90.5%) were discharged on reporting, including two critically ill patients. No mortality occurred in 21 treated patients. The study authors concluded that TCZ was an effective treatment for patients with severe covd-19 (Xu et al (2020), supra).
An adaptive 2/3 phase, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of sarilumab against hospitalized patients with covd-19, which can be seen in: https:// www.clinicaltrials.gov/ct2/show/NCT04315298. Sarilumab is a human monoclonal antibody directed against interleukin 6 receptor.
Disclosure of Invention
The present invention relates to a method of treating viral pneumonia in a patient comprising administering to the patient an effective amount of a combination of tolizumab and adefovir.
In one embodiment, the pneumonia is a viral pneumonia.
In one embodiment, the pneumonia is a coronavirus pneumonia.
In one embodiment, the pneumonia is a covd-19 pneumonia.
In one embodiment, the pneumonia is severe pneumonia.
In one embodiment, the pneumonia is severe covd-19 pneumonia.
In one embodiment, the patient does not have elevated IL-6 levels.
In one embodiment, no patients were found to have elevated IL-6 levels by laboratory testing.
In one embodiment, the patient has an alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST) >5 and < upper normal limit (ULN) of 10.
In one embodiment, the method treats Acute Respiratory Distress (ARDS) in a patient.
Drawings
Fig. 1 depicts a method of clinical testing in example 1.
Detailed Description
I. Definition of the definition
Abbreviations that may be used in this specification:
for purposes herein, "inflammation" refers to an immune defense against infection characterized by increased local blood flow, leukocyte migration, and chemical toxin release. Inflammation is one way the body protects itself against infection. Clinical features of inflammation include redness, heat, swelling, pain, and loss of function in the body part. Systemic inflammation may lead to fever, joint and muscle pain, organ dysfunction and discomfort.
"pneumonia" refers to inflammation of one or both lungs, accompanied by dense areas of lung inflammation. The present invention relates to pneumonia caused by viral infection. Symptoms of pneumonia may include fever, chill, expectoration, chest pain, and shortness of breath. In one embodiment, pneumonia has been confirmed by chest X-ray or computed tomography (CT scan).
"severe pneumonia" refers to pneumonia in which the heart, kidneys or circulatory system is at risk of failure, or the lungs are unable to re-ingest sufficient oxygen and develop into Acute Respiratory Distress Syndrome (ARDS). Patients with severe pneumonia are typically hospitalized and may be in an Intensive Care Unit (ICU). In general, patients have severe dyspnea, respiratory distress, and shortness of breath>30 times/min) and hypoxia, optionally with fever. Cyanosis can occur in children. In this definition, diagnosis is clinical and radiological imaging is used to rule out complications. In one embodiment, a patient suffering from severe pneumonia has impaired lung function, which is measured by peripheral capillary oxygen saturation (SpO 2 ) And (5) determining. In one embodimentIn patients with severe pneumonia, patients with impaired pulmonary function, which is characterized by a ratio of arterial oxygen partial pressure to inhaled oxygen partial pressure (PaO 2/FiO) 2 ) And (5) determining. In one embodiment, a patient suffering from severe pneumonia has an SpO of 93% or less 2 . In one embodiment, a patient suffering from severe pneumonia has<PaO2/FiO of 300mmHg 2 (optionally according to PaO 2/FiO) 2 x [ atmospheric pressure (mmHg)/760)]Adjustments are made for high altitude areas). In one embodiment, the patient has respiratory distress (RR. Gtoreq.30 breaths/min). In one embodiment, a patient has a lung in imaging >50% of lesions.
"Critical pneumonia" refers to a patient suffering from severe pneumonia that is suffering from respiratory failure, shock and/or organs. In one embodiment, the patient suffering from severe pneumonia requires mechanical ventilation.
"Mild pneumonia" is manifested as symptoms of upper respiratory tract viral infection, including mild fever, cough (dry cough), sore throat, nasal obstruction, discomfort, headache, muscle pain, or malaise. There are no signs or symptoms of more severe diseases, such as dyspnea.
In "moderate pneumonia," respiratory symptoms such as cough and shortness of breath (or shortness of breath in children) occur without signs of severe pneumonia. Patients with moderate pneumonia may be hospitalized but not in the ICU or with a ventilator.
"acute respiratory syndrome" or "ARDS" refers to a life threatening pulmonary condition that will prevent adequate oxygen from entering the lungs and into the blood. In one embodiment, the diagnosis of ARDS is based on the following criteria: acute onset, bilateral lung infiltration on chest radiographs of non-cardiac origin, and PaO/FiO ratios of <300mmHg. In one embodiment, ARDS is "mild ARDS" characterized by PaO2/FiO2 of 200 to 300mmHg. In one embodiment, the ARDS is a "moderate ARDS" characterized by PaO2/FiO2 of 100 to 200 mmHg. In one embodiment, the ARDS is a "severe ARDS" characterized by PaO2/FiO2<100 mmHg.
"viral pneumonia" refers to pneumonia caused by the entry of one or more viruses into a patient. In one embodiment, the virus is a DNA virus. In one embodiment, the virus is an RNA virus. Examples of viruses considered herein that cause viral pneumonia include, inter alia, viruses caused by: human Immunodeficiency Virus (HIV), hepatitis b virus, hepatitis c virus, influenza virus (including H1N1 or "swine influenza" and H5N1 or "avian influenza"), zika virus, rotavirus, rabies virus, west nile virus, herpes virus, adenovirus, respiratory Syncytial Virus (RSV), norovirus, rotavirus, astrovirus, rhinovirus, human Papilloma Virus (HPV), poliovirus, dengue, ebola virus, and coronavirus. In one embodiment, the viral pneumonia is caused by coronavirus.
A "coronavirus" is a virus that infects humans and causes respiratory tract infections. Coronaviruses that can cause pneumonia in patients include, but are not limited to, beta coronaviruses that cause Middle East Respiratory Syndrome (MERS), beta coronaviruses that cause Severe Acute Respiratory Syndrome (SARS), and covd-19 viruses.
"covd-19" refers to a virus that causes a disease, which is often characterized by fever, cough, and shortness of breath, and may develop into pneumonia and respiratory failure. In one embodiment, a patient with covd-19 is identified by a positive Polymerase Chain Reaction (PCR) test (e.g., real-time PCT, RT-PCT test) from a sample of the patient (e.g., respiratory tract, blood, urine, stool, other body fluid sample). In one embodiment, the COVID-19 nucleic acid sequence has been determined to be highly homologous to COVID-19. In one embodiment, the patient has a covd-19 specific antibody (e.g., igG and/or IgM antibodies), e.g., as determined by Immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), and the like. Synonyms for covd-19 include, but are not limited to, "novel coronavirus", "2019 novel coronavirus" and "2019-nCoV".
The term "patient" herein refers to a human patient.
The "intravenous" or "iv" dose, administration or formulation of the drug is administered intravenously, for example by infusion.
The "subcutaneous" or "sc" dose, administration or formulation of the drug is administered under the skin, for example via a pre-filled syringe, an auto-injector or other device.
The "weight-based dose" of a drug refers to a dose based on the weight of the patient. In a preferred embodiment, when the drug is tolizumab, the weight-based dose is 8mg/kg (optionally a dose of +.800 mg).
"fixed dose" of a drug refers to a dose administered without regard to the patient's weight.
For purposes herein, a "clinical state" refers to the health of a patient. Examples include the patient being improved or worsened. In one embodiment, the clinical status is based on an ordered list of clinical status. In one embodiment, the clinical status is not based on whether the patient has fever.
An "ordered list of clinical states" refers to a list used to quantify dimensionless results. They include results that may include a single point in time, or changes that occur between two points in time may be checked. In one embodiment, the two time points are "day 1" (when a first dose, e.g., 8mg/kg, of an IL6 antagonist such as tolizumab is administered) compared to "day 28" (when the patient is assessed), and optionally "day 60 (when the patient is further assessed). The order table includes various "categories," each of which evaluates a particular state or result. In one embodiment, the order table is a "7-category order table".
In one embodiment, the "7-category ordering table" includes the following categories for assessing patient status:
1. discharge (or "ready to discharge", e.g. as evidenced by normal body temperature and respiratory rate, ambient air or oxygen saturation stabilization with 2L oxygen supplementation)
2. non-ICU hospital ward (or "ready to hospital ward") and does not require supplemental oxygen
3. non-ICU hospital ward (or "ready to hospital ward") and need to be supplemented with oxygen
ICU or non-ICU hospital ward, requiring non-invasive ventilation or high flow of oxygen
Icu, requiring intubation and mechanical ventilation
Icu, requiring ECMO or mechanical ventilation and additional organ support (e.g. vasopressors, renal replacement therapy)
7. Death.
For purposes herein, "standard of care" or "SOC" refers to a therapeutic method or medicament typically used to treat patients suffering from pneumonia (e.g., viral pneumonia, such as covd-19 pneumonia), including, inter alia, supportive care, administration of one or more antiviral agents, and/or administration of one or more corticosteroids.
"supportive care" includes, but is not limited to: respiratory support (e.g., oxygen therapy via a mask or nasal catheter, high flow nasal oxygen therapy or non-invasive mechanical ventilation, invasive mechanical ventilation via extracorporeal membrane pulmonary oxygenation (ECMO), etc.); circulatory support (e.g., fluid resuscitation, microcirculatory augmentation, vasoactive drugs); renal replacement therapy; plasma therapy; blood purification therapy; xuebijing injection (e.g., 100 mL/day, twice a day); microecologics (e.g., probiotics, prebiotics, and synbiotics); non-steroidal anti-inflammatory drugs (NSAIDs); a herbal medicine; plasma (e.g., convalescence plasma), and the like.
"antiviral" agents include, but are not limited to: interferon alpha, lopinavir, ritonavir, lopinavir/ritonavir, radciclovir, ribavirin, hydroxychloroquine or chloroquine (with or without azithromycin), wu Minuo, and the like.
"corticosteroid" refers to any one of several synthetic or naturally occurring substances having the general chemical structure of a steroid that mimics or enhances the action of a naturally occurring corticosteroid. Examples of synthetic corticosteroids include prednisone, prednisolone (including methylprednisolone such as methylprednisolone sodium succinate), dexamethasone or dexamethasone triamcinolone, hydrocortisone and betamethasone. In one embodiment, the corticosteroid is selected from prednisone, methylprednisolone, hydrocortisone, and dexamethasone. In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, the corticosteroid is a "low dose" glucocorticoid (e.g., 1-2 mg/kg/day methylprednisolone, e.g., for 3-5 days).
"human interleukin 6" (abbreviated "IL-6") herein is a cytokine, also known as B-cell stimulating factor 2 (BSF-2) or interferon beta-2 (IFNB 2), hybridoma growth factors, and CTL differentiation factors. IL-6 was found to be a differentiation factor that contributes to B cell activation (Hirano et al, nature 324:73-76 (1986)), and was later found to be a multifunctional cytokine that affects the function of a number of different cell types (Akira et al, adv. In Immunology 54:1-78 (1993)). Naturally occurring variants of human IL-6 are known and are encompassed within this definition. Human IL-6 amino acid sequence information has been disclosed, see for example www.uniprot.org/uniprot/P05231.
An "IL6 antagonist" refers to an agent that inhibits or blocks the biological activity of IL6 via binding to human IL6 or a human IL6 receptor. In one embodiment, the IL6 antagonist is an antibody. In one embodiment, the IL6 antagonist is an antibody that binds to an IL6 receptor. Antibodies that bind the IL-6 receptor include tolizumab (including intravenous (iv) and subcutaneous (sc) formulations thereof) (Chugai, roche, genentech), sha Lizhu mab (Chugai, roche, genentech), sarilumab (Sanofi, regeneron), NI-1201 (Novimmune and Tiziana), and Fu Bali mab (Ablynx). In one embodiment, the IL6 antagonist is a monoclonal antibody that binds IL 6. Antibodies that bind IL-6 include western Lu Kushan antibody (Centecor, janssen), ololomab (UCB), cladagumab (BMS and Alder), steuximab (Janssen), EBI-031 (Eleven Biotherapeutics and Roche). In some embodiments, the IL6 antagonist is oxazepine.
For purposes herein, "human interleukin 6 receptor" (abbreviated as "IL-6R") refers to a receptor that binds IL-6, including both membrane-bound IL-6R (mIL-6R) and soluble IL-6R (sIL-6R). IL-6R may be combined with interleukin 6 signal transduction glycoprotein 130 to form an active receptor complex. Alternative splice transcriptional variants encoding different isoforms of IL-6 have been reported and are included in this definition. The amino acid sequence structure of human IL-6R and its extracellular domain has been described; see, for example, yamasaki et al Science,241:825 (1988).
"neutralizing" anti-IL-6R antibodies herein are antibodies that bind to IL-6R and are capable of inhibiting the ability of IL-6 to bind to and/or activate IL-6R to a measurable extent. Torpedo mab is one example of neutralizing an anti-IL-6R antibody.
"Tozumaab" or "TCZ" is a recombinant humanized monoclonal antibody, which binds to human interleukin 6 receptor (IL-6R). It is an IgG1 kappa (gamma 1, kappa) antibody with two heavy and two light chains forming two antigen binding sites. In a preferred embodiment, the light and heavy chain amino acid sequences of tolizumab comprise SEQ ID No.1 and 2, respectively.
"native sequence" protein herein refers to a protein comprising the amino acid sequence of a protein found in nature, including naturally occurring variants of the protein. The term as used herein includes proteins isolated or recombinantly produced from their natural sources.
The term "antibody" is used herein in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.
An "antibody fragment" as used herein includes a portion of an intact antibody that retains the ability to bind an antigen. Examples of antibody fragments include Fab, fab ', F (ab') 2 And Fv fragments; a diabody antibody; a linear antibody; a single chain antibody molecule; and multispecific antibodies formed from antibody fragments.
As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind to the same epitope, except for possible variants that may be produced during production of the monoclonal antibody, which variants are typically present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to specificity, monoclonal antibodies are advantageous in that they are synthesized without contamination by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies according to the invention may be prepared by the hybridoma method described first by Kohler et al, nature,256:495 (1975), or may be prepared by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). "monoclonal antibodies" can also be isolated from phage antibody libraries using techniques such as those described by Clackson et al, nature,352:624-628 (1991) and Marks et al, J.mol.biol.,222:581-597 (1991). Specific examples of monoclonal antibodies herein include chimeric antibodies, humanized antibodies, and human antibodies, including antigen-binding fragments thereof.
Monoclonal antibodies herein include, in particular, "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, and the remainder of one or more chains is identical or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; morrison et al, proc. Natl. Acad. Sci. USA,81:6851-6855 (1984)). Chimeric antibodies of interest herein include "primatized" antibodies comprising variable domain antigen binding sequences derived from a non-human primate (e.g., such as baboon, rhesus or cynomolgus) and human constant region sequences (U.S. patent No. 5,693,780).
A non-human (e.g., murine) antibody in a "humanized" form is a chimeric antibody that comprises minimal sequences derived from a non-human immunoglobulin. In most cases, humanized antibodies are human immunoglobulins (recipient antibody) in which residues in a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired specificity, affinity and function. In some cases, framework Region (FR) residues of the human immunoglobulin are replaced with corresponding non-human residues. In addition, the humanized antibody may comprise residues that are not present in the recipient antibody or the donor antibody. These modifications are intended to further refine antibody performance. Generally, a humanized antibody will comprise substantially at least one, and typically two, variable domains, of a population, in which all or substantially all of the hypervariable regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR is that of a human immunoglobulin sequence, except for the FR substitutions referred to above. The humanized antibody also optionally comprises at least a portion of an immunoglobulin constant region, typically a human immunoglobulin. See Jones et al Nature 321:522-525 (1986) for more details; riechmann et al Nature 332:323-329 (1988); and Presta, curr.Op.struct.biol.2:593-596 (1992). Humanized antibodies herein specifically include "remodeled" IL-6R antibodies as described in U.S. patent No. 5,795,965, which is expressly incorporated herein by reference.
Herein, "human antibody" is an antibody comprising an amino acid sequence structure corresponding to that of an antibody obtainable from human B cells, and includes antigen-binding fragments of human antibodies. Such antibodies may be identified or prepared by a variety of techniques, including but not limited to: transgenic animals (e.g., mice) capable of producing human antibodies without endogenous immunoglobulin production after immunization are produced (see, e.g., jakobovits et al, proc. Natl. Acad. Sci. USA,90:2551 (1993); jakobovits et al, nature,362:255-258 (1993); bruggermann et al, year in immunoo., 7:33 (1993); and U.S. Pat. Nos. 5,591,669, 5,589,369, and 5,545,807); selection from phage display libraries expressing human antibodies or human antibody fragments (see, e.g., mcCafferty et al, nature 348:552-553 (1990), johnson et al, current Opinion in Structural Biology 3:564-571 (1993), clackson et al, nature,352:624-628 (1991), marks et al, J.mol. Biol.222:581-597 (1991), griffith et al, EMBO J.12:725-734 (1993), U.S. Pat. Nos. 5,565,332 and 5,573,905); produced via in vitro activated B cells (see U.S. Pat. nos. 5,567,610 and 5,229,275); and isolating from the hybridoma producing the human antibody.
A "multispecific antibody" herein is an antibody that has binding specificity for at least two different epitopes. Exemplary multispecific antibodies can bind to two non-IL-6RHomoepitopes. Alternatively, the anti-IL-6R antibody binding arm may be combined with an arm that binds to a trigger molecule on leukocytes, such as a T cell receptor molecule (e.g., CD2 or CD 3), or an Fc receptor of IgG (fcγr), such as fcγri (CD 64), fcγrii (CD 32), and fcγriii (CD 16), thereby focusing the cellular defense mechanisms on the receptor. Multispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g., F (ab') 2 Bispecific antibodies). Engineered antibodies having three or more (preferably four) functional antigen binding sites are also contemplated (see, e.g., US application No. US 2002/0004587 A1,Miller et al).
Antibodies herein include "amino acid sequence variants" having altered antigen binding or biological activity. Examples of such amino acid changes include antibodies with increased affinity for antigen (e.g., affinity matured antibodies), as well as antibodies with altered Fc regions (if present), e.g., with altered (increased or decreased) antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC) (see, e.g., WO00/42072, presta, l. And WO 99/51642, iduosogie et al); and/or increased or decreased serum half-life (see, e.g., WO00/42072, presta, l.).
The antibodies herein may be conjugated to a "heterologous molecule," for example, to increase half-life or stability or otherwise improve the antibody. For example, the antibody may be attached to one of a variety of non-protein polymers, such as polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylene, or a copolymer of polyethylene glycol and polypropylene glycol. Antibody fragments, such as Fab', linked to one or more PEG molecules are exemplary embodiments of the invention.
An antibody herein may be a "glycosylation variant" such that any carbohydrate (if present) attached to the Fc region is altered. Antibodies having mature carbohydrate structures, which lack fucose linkage to the Fc region of the antibody, are described, for example, in U.S. patent application No. US 2003/0157108 (Presta, l.). See also US 2004/0093621 (Kyowa Hakko Kogyo co., ltd). Antibodies having bisecting N-acetylglucosamine (GlcNAc) in the carbohydrate attached to the Fc region of the antibody are mentioned in WO 2003/011878, jean-Maiset et al and U.S. Pat. No. 6,602,684, umana et al. Antibodies in which at least one galactose residue in the oligosaccharide is attached to the Fc region of the antibody are reported in WO 1997/30087, patel et al. Antibodies with altered carbohydrate attachment to their Fc region are also described in WO 1998/58964 (Raju, S.) and WO 1999/22764 (Raju, S.). See also US 2005/0123946 (Umana et al), which describes antibodies with modified glycosylation.
As used herein, the term "hypervariable region" refers to the amino acid residues in an antibody that are responsible for antigen binding. Hypervariable regions comprise amino acid residues from the "complementarity determining regions" or "CDRs" (e.g., residues 24-34 (L1), 50-56 (L2), and 89-97 (L3) in the light chain variable domain, and 31-35 (H1), 50-65 (H2), and 95-102 (H3) in the heavy chain variable domain; kabat et al Sequences of Proteins of Immunological Interest, 5 th edition Public Health Service, national Institutes of Health, bethesda, MD. (1991)) and/or those residues from the "hypervariable loop" (e.g., residues 26-32 (L1), 50-52 (L2), and 91-96 (L3) in the light chain variable domain, and residues 26-32 (H1), 53-55 (H2), and 96-101 (H3) in the heavy chain variable domain; chothia and Lesk J.mol. Biol.196:901-917 (1987)). "framework" or "FR" residues are those variable domain residues other than the hypervariable region residues defined herein. The hypervariable region of tobulimib comprises:
L1-Arg Ala Ser Gln Asp Ile Ser Tyr Leu Asn(SEQ ID NO:3)；
L2-Tyr Thr Ser Arg Leu His Ser(SEQ ID NO:4)；
L3–Gln Gly Asn Thr Leu Pro Tyr Thr(SEQ ID NO:5)；
H1–Ser Asp His Ala Trp Ser(SEQ ID NO:6)；
H2-Tyr Ile Ser Tyr Ser Gly Ile Thr Tyr Asn Pro Ser Leu Lys Ser (SEQ ID NO: 7); and
H3-Ser Leu Ala Arg Thr Ala Met Asp Tyr(SEQ ID NO:8)。
in one embodiment herein, the IL-6R antibody comprises a hypervariable region of tolizumab.
A "full length antibody" is an antibody comprising an antigen binding variable region (CL) and heavy chain constant domains CH1, CH2 and CH 3. The constant domain may be a natural sequence constant domain (e.g., a human natural sequence constant domain) or an amino acid sequence variant thereof. Preferably, the full length antibody has one or more effector functions. Tozumaab is one example of a full length antibody.
A "naked antibody" is an antibody (as defined herein) that is not conjugated to a heterologous molecule such as a cytotoxic moiety, polymer, or radiolabel.
Antibody "effector functions" refer to those biological activities attributed to the Fc region of an antibody (native sequence Fc region or amino acid sequence variant Fc region). Examples of antibody effector functions include C1q binding, complement Dependent Cytotoxicity (CDC), fc receptor binding, antibody dependent cell-mediated cytotoxicity (ADCC), and the like.
Full-length antibodies can be classified into different "classes" according to the amino acid sequence of their heavy chain constant domains. There are five major classes of full length antibodies: igA, igD, igE, igG and IgM, and several of these classes can be further divided into "subclasses" (isotypes), e.g., igGl, igG2, igG3, igG4, igA, and IgA2. The heavy chain constant domains corresponding to the different classes of antibodies are called α, δ, ε, γ and μ, respectively. Subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
As used herein, the term "recombinant antibody" refers to an antibody (e.g., chimeric, humanized or human antibody or antigen-binding fragment thereof) expressed by a recombinant host cell comprising a nucleic acid encoding the antibody. Examples of "host cells" for producing recombinant antibodies include: (1) Mammalian cells, such as Chinese Hamster Ovary (CHO), COS, myeloma cells (including Y0 and NS0 cells), baby Hamster Kidney (BHK), hela and Vero cells; (2) insect cells, e.g., sf9, sf21, and Tn5; (3) Plant cells, such as plants belonging to the genus Nicotiana (Nicotiana), such as tobacco (Nicotiana tabacum); (4) Yeast cells, for example, those belonging to the genus Saccharomyces (e.g., saccharomyces cerevisiae (Saccharomyces cerevisiae)) or Aspergillus (e.g., aspergillus niger (Aspergillus niger)). (5) Bacterial cells, such as E.coli (Escherichia coli) cells or Bacillus subtilis (Bacillus subtilis) cells, and the like.
As used herein, "specifically binds" or "specifically binds to" refers to the selective or preferential binding of an antibody to an IL-6R antigen. Preferably, the binding affinity for antigen is 10 -9 Kd value of mol/l or less (e.g. 10 -10 mol/l), preferably 10 -10 mol/l or less (e.g. 10 -12 Kd value of mol/l). Using standard binding assays (e.g. surface plasmon resonance techniquesTo determine binding affinity.
Examples of "non-steroidal anti-inflammatory drugs" or "NSAIDs" include aspirin, acetylsalicylic acid, ibuprofen, flurbiprofen, naproxen, indomethacin, sulindac, tolmetin, phenylbutazone, diclofenac, ketoprofen, benzoate, mefenamic acid, methotrexate, fenbufen, triamcinolone; COX-2 inhibitors such as celecoxib4- (5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) benzenesulfonamide, valdecoxib +.>Meloxicam (>GR 253035 (Glaxo wellcom); and MK966 (Merck Sharp)&Dohme), including salts and derivatives thereof, and the like. The specific embodiment comprises the following steps: aspirin, naproxen, ibuprofen, indomethacin, and tolmetin.
The expression "effective amount" refers to an amount of an IL6 antagonist (e.g., an IL6 receptor antibody, such as tolizumab) effective in treating pneumonia (e.g., viral pneumonia, including covd-19 pneumonia) and/or treating Acute Respiratory Distress Syndrome (ARDS).
The term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective, and that is free of additional components that have unacceptable toxicity to the subject to whom the formulation is to be administered. Such formulations are sterile formulations. In one embodiment, the formulation is for intravenous (iv) administration. In another embodiment, the formulation is for subcutaneous (sc) administration.
"sterile" formulations are sterile or free of all living microorganisms and spores thereof.
"liquid formulation" or "aqueous formulation" according to the present invention means a formulation that is liquid at a temperature of at least about 2 to about 8 ℃.
The term "lyophilized formulation" means a formulation that is dried by freezing the formulation and subsequently sublimating ice from the frozen content by any freeze-drying method known in the art, such as commercially available freeze-drying equipment. Such formulations may be reconstituted in a suitable diluent such as water, sterile water for injection, saline solution, and the like, to form a reconstituted liquid formulation suitable for administration to a subject.
"package insert" is used to refer to instructions generally included in commercial packages of therapeutic products that contain information concerning the indications, usage, dosage, administration, contraindications, other therapeutic products used in combination with the products within the package, and/or warnings concerning the use of such therapeutic products, and the like.
An "elevated" level of a biomarker means that the amount of the biomarker in a patient is above the Upper Limit of Normal (ULN).
"elevated IL6 level" is ≡15pg/mL, or ≡10pg/mL or >7pg/mL, e.g. as measured by enzyme-linked immunosorbent assay (ELISA) of a blood sample from the patient. In one embodiment, the "normal" IL6 level is considered 7pg/mL.
A patient "found no elevated IL-6 levels by laboratory testing" has been treated according to the methods herein, regardless of his or her IL-6 levels. In one embodiment, such patients do not have elevated IL6 levels.
"Redexivir" is an antiviral drug, nucleotide analog, in particular an adenosine analog, which can be inserted into the viral RNA strand, resulting in premature termination thereof. Its molecular formula is C 27 H 35 N 6 O 8 P and IUPAC name (2S) -2- [ [ [ (2R, 3S,4R, 5R) -5- (4-aminopyrrole [2, 1-f)][1,2,4]Triazin-7-yl) -5-cyano-3, 4-dihydroxyoxapent-2-yl]Methoxy-phenoxy phosphoryl group]Amino group]Propionic acid 2-ethylbutyl. The laboratory name of Swedeciclovir is GS-5734, with CAS number 1809249-37-3. Which is described in us patent No. 9,724,360 and manufactured by Gilead Sciences.
Production of IL6 antagonists
IL6 antagonists contemplated herein include antagonists that bind to IL6 or IL6 receptor.
In one embodiment, the IL6 antagonist is an antibody.
In one embodiment, the IL6 antagonist is an antibody that binds to an IL6 receptor.
In one embodiment, the IL6 antagonist is an antibody that binds to a membrane-bound IL6 receptor and a soluble IL6 receptor.
In one embodiment, the IL6 antagonist blocks IL-6/IL-6 receptor complex and depletes circulating levels of IL-6 in the blood.
Antibodies that bind the IL-6 receptor include tolizumab (including intravenous (iv) and subcutaneous (sc) formulations thereof) (Chugai, roche, genntech), sha Lizhu mab (Chugai, roche, genntech), sarilumab (Sanofi, regeneron), NI-1201 or TZLS-501 (Novimmune and Tiziana) and Fu Bali beadmab (Ablynx).
In one embodiment, the IL6 antagonist is tolizumab.
Torpedo mab, also known as Myeloma Receptor Antibody (MRA), is a recombinant humanized monoclonal antibody that selectively binds to the human interleukin 6 receptor (IL-6R). It is an IgG1 kappa (gamma 1, kappa) antibody with a typical H 2 L 2 Structure is as follows. The tobrazumab molecule consists of two heterodimers. Each heterodimer consists of one heavy (H) and one light (L) polypeptide chain. Four polypeptide chains are linked intramolecularly and intermolecularly by disulfide bonds. The molecular formula and theoretical molecular weight of tolizumab are as follows:
The molecular formula: c (C) 6428 H 9976 N 1720 O 2018 S 42 (only the polypeptide part)
Molecular weight: 144,985da (only polypeptide part).
The light chain amino acid sequences deduced from the complementary deoxyribonucleic acid (cDNA) sequences and confirmed by liquid chromatography-mass spectrometry (LC-MS) peptide mapping are shown in SEQ ID No.1 and 2. Five light chain cysteine residues per heterodimer are involved in two intrachain disulfide bonds and one interchain disulfide bond:
intra-chain disulfide bonds: cys (Cys) L23 -Cys L88 And Cys L134 -Cys L194
A bond between the heavy and light chains: cys (Cys) L214 And Cys H222
The distribution of disulfide bonds was based on sequence homology with other IgG1 antibodies and confirmed by liquid chromatography mass spectrometry (LC-MS) peptide mapping using materials from the fourth generation (G4) process. Cys (Cys) Lx And Cys Hx The cysteine residues at the x positions of the light and heavy chains, respectively.
Amino acid sequence of molecular L chain of tobrazumab SEQ ID NO.1
/>
Note that: the entire sequence has been determined by LC-MS peptide mapping.
The heavy chain amino acid sequence deduced from the complementary deoxyribonucleic acid (cDNA) sequence and confirmed by amino acid sequencing is shown in SEQ ID NO. 2. Eleven heavy chain cysteine residues per heterodimer are involved in four intra-chain disulfide bonds, two inter-chain disulfide bonds between two heavy chains, and a third inter-chain disulfide bond between the heavy and light chains of each heterodimer:
Intra-chain disulfide bonds: cys (Cys) H22 -Cys H96 、Cys H146 -Cys H202 、Cys H263 -Cys H323 And Cys H369 -Cys H427
A bond between two heavy chains: cys (Cys) H228 -Cys H228 And Cys H231 -Cys H231
A bond between the heavy and light chains: cys (Cys) L214 -Cys H222
The partitioning of disulfide bonds was based on sequence homology with other IgG1 antibodies and was confirmed by LC-MS peptide mapping using materials from the G4 process.
Amino acid sequence of H chain of tobrazumab molecule of SEQ ID NO.2
Note that: the entire sequence has been determined by LC-MS peptide mapping. The N-terminus of the heavy chain has been determined to be predominantly pyroglutamic acid residue (pE).
In one embodiment, the IL6 antagonist is Sha Lizhu mab. Sha Lizhu monoclonal antibody (also referred to as SA 237) is a humanized monoclonal antibody that binds to the IL6 receptor. See U.S. patent No. US 8,562,991.
In one embodiment, the IL6 antagonist is a human antibody that binds IL6 and is referred to as TZLS-501 (Tiziana) or NI-1201 (Novimnune).
In one embodiment, the IL6 antagonist is a monoclonal antibody that binds IL 6.
Antibodies that bind IL-6 include western Lu Kushan antibody (Centecor, janssen), ololomab (UCB), cladagumab (BMS and Alder), steuximab (Janssen), EBI-031 (Eleven Biotherapeutics and Roche).
In some embodiments, the IL6 antagonist is oxazepine. Oxiracecadre is a recombinant protein that fuses the extracellular domain of the IL-6R beta (glycoprotein 130, gp 130) signaling subunit of the IL-6 receptor with a human IgG Fc fragment. The complete construct is a dimer of covalently linked identical peptide chains. Mechanically, oxiracetam acts as an inhibitor of the IL-6 signaling pathway. Oxiracetam inhibits signaling through the soluble IL-6 receptor (sIL-6R).
In preferred embodiments, the methods and articles of the invention use or incorporate antibodies that bind to human IL-6R. The IL-6R antigen used to generate or screen antibodies may be, for example, a soluble form of IL-6R containing the desired epitope or a portion thereof (e.g., an extracellular domain). Alternatively or additionally, cells expressing IL-6R on their cell surface can be used to generate or screen antibodies. Other forms of IL-6R that can be used to generate antibodies will be apparent to those skilled in the art.
In one embodiment, the antibody is an antibody fragment, and various such fragments are disclosed above.
In another embodiment, the antibody is a whole or full length antibody. Complete antibodies can be classified into different classes according to the amino acid sequence of their heavy chain constant domains. There are five main classes of intact antibodies: igA, igD, igE, igG and IgM, and several of these classes can be further divided into "subclasses" (isotypes), such as IgG1, igG2, igG3, igG4, igA, and IgA2. The heavy chain constant domains corresponding to the different classes of antibodies are called α, δ, ε, γ and μ, respectively. Subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. In a preferred embodiment, the anti-IL-6R antibody is an IgG1 or IgM antibody.
Techniques for producing antibodies are known and examples are provided in the definitions section above in this document. In preferred embodiments, the antibody is a chimeric, humanized or human antibody or antigen binding fragment thereof. Preferably, the antibody is a humanized full length antibody.
There are a variety of techniques available to determine the binding of antibodies to IL-6R. One such assay is an enzyme-linked immunosorbent assay (ELISA) for confirming the ability to bind to human IL-6R. See, for example, U.S. patent No. 5,795,965. According to this assay, IL-6R coated plates (e.g., recombinant sIL-6R) are incubated with a sample containing anti-IL-6R antibodies, and binding of the antibodies to sIL-6R is determined.
Preferably, the anti-IL-6R antibody neutralizes IL-6 activity, for example, by inhibiting IL-6 binding to IL-6R. Exemplary methods for assessing such inhibition are disclosed, for example, in U.S. Pat. nos. 5,670,373 and 5,795,965. According to this method, antibodies are evaluated for their ability to compete with IL-6 for IL-6R. For example, plates are coated with IL-6R (e.g., recombinant sIL-6R), a sample comprising an anti-IL-6R antibody with labeled IL-6 is added, and the ability of the antibody to block binding of labeled IL-6 to IL-6R is measured. See, U.S. patent No. 5,795,965. Alternatively or additionally, the identification of IL-6 binding to membrane-bound IL-6R was performed according to the method of Taga et al J.Exp.Med.,166:967 (1987). Assays using the IL-6 dependent human T cell leukemia line KT3 to confirm neutralization activity are also available, see U.S. Pat. No. 5,670,373 and Shimizu et al Blood 72:1826 (1988).
Non-limiting examples of anti-IL-6R antibodies herein include PM-1 antibodies (Hirata et al, J. Immunol.143:2900-2906 (1989)), AUK12-20, AUK64-7, and AUK146-15 (U.S. Pat. No. 5,795,965), as well as humanized variants thereof, including, for example, tolizumab. See, U.S. patent No. 5,795,965. Preferred examples of reconstituted human antibodies for use in the present invention include humanized or remodeled anti-interleukin (IL-6) receptor antibody (hPM-1 or MRA) (see U.S. Pat. No. 5,795,965).
The antibodies herein are preferably recombinantly produced in a host cell transformed with nucleic acid sequences encoding the heavy and light chains thereof (e.g., wherein the host cell has been transformed with one or more vectors containing the nucleic acids). Preferred host cells are mammalian cells, most preferably Chinese Hamster Ovary (CHO) cells.
III pharmaceutical preparation
Therapeutic formulations of antibodies for use according to the invention for storage in lyophilized formulations or aqueous solutions are prepared by mixing antibodies of the desired purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences, 16 th edition, osol, a.ed. (1980)). Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethyldiammonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl p-hydroxybenzoates such as methyl or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; m-cresol); a low molecular weight (less than about 10 residues) polypeptide; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, e.g. glycine, glutamine Amide, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc protein complexes); and/or nonionic surfactants, e.g. TWEEN TM 、PLURONICS TM Or polyethylene glycol (PEG).
The formulations herein may also contain more than one active compound as desired, preferably those active compounds having complementary activities that do not adversely affect each other. The type and effective amount of such drugs depends, for example, on the amount of antibody present in the formulation and on clinical parameters of the subject. Exemplary such agents are discussed below.
The active ingredient may be embedded in microcapsules (e.g., hydroxymethyl cellulose or gelatin microcapsules and poly (methyl methacrylate) microcapsules, respectively) prepared, for example, by coacervation techniques or by interfacial polymerization, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16 th edition, osol, a. Ed., 1980.
A slow release preparation may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl methacrylate) or polyvinyl alcohol), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma ethyl L-glutamic acid, nondegradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT TM (injectable microspheres consisting of lactic acid-glycolic acid copolymer and leuprorelin acetate) and poly-D- (-) -3-hydroxybutyric acid.
The formulation to be used for in vivo administration must be sterile. This is easily accomplished by filtration through sterile filtration membranes.
In one embodiment, the formulation is suitable for intravenous (iv) infusion, e.g., the tolizumab iv formulation disclosed in U.S. patent nos. 8,840,884 and 9,051,384. In one embodiment, the tolizumab iv formulation is a sterile, transparent, colorless to pale yellow, preservative-free solution for further dilution prior to intravenous infusion, at a pH of about 6.5. In one embodiment, the formulation of tolizumab iv is provided in a single dose vial, is formulated with disodium phosphate dodecahydrate/sodium phosphate monobasic buffer solution, and is available in a concentration of 20mg/mL, comprising 80mg/4mL, 200mg/10mL, or 400mg/20mL of tolizumab. In one embodiment, each mL of tobrazumab iv solution contains polysorbate 80 (0.5 mg), sucrose (50 mg), and water for injection, USP.
In one embodiment, the formulation is suitable for subcutaneous (sc) administration, for example, as in the tolizumab sc formulation of U.S. patent 8,568,720. In one embodiment, the tolizumab sc formulation is a sterile, transparent, colorless to yellowish, preservative-free histidine buffer solution with a pH of about 6.0 for subcutaneous use. In one embodiment, the tolizumab sc formulation is provided in a single-dose, ready-to-use, 0.9mL pre-filled syringe (PFS) or a single-dose, ready-to-use, 0.9mL auto-injector with a needle safety device. In one example, a formulation of tolizumab sc delivers 162mg of tolizumab, L-arginine hydrochloride (19 mg), L-histidine (1.52 mg), L-histidine hydrochloride monohydrate (1.74 mg), L-methionine (4.03 mg), polysorbate 80 (0.18 mg) and water for injection.
Preferably, the formulation is isotonic.
Therapeutic use of anti-IL-6 antagonists
The present invention provides a method of treating pneumonia in a patient comprising administering to the patient a (first) weight-based intravenous dose of tolizumab, wherein the weight-based dose is 8mg/kg tolizumab (e.g., wherein ∈800mg tolizumab is administered to the patient).
In one embodiment, the pneumonia is severe pneumonia.
In one embodiment, the pneumonia is a critical pneumonia.
In one embodiment, the pneumonia is a moderate pneumonia.
In one embodiment, the pneumonia is moderate-severe pneumonia.
In one embodiment, the pneumonia is a viral pneumonia.
In one embodiment, the viral pneumonia is a coronavirus pneumonia.
In one embodiment, the pneumonia is a covd-19 pneumonia, a middle east respiratory syndrome (MERS-CoV) pneumonia, or a severe acute respiratory syndrome (SARS-CoV) pneumonia.
In one embodiment, the viral pneumonia is a covd-19 pneumonia.
In one embodiment, the viral pneumonia is severe covd-19 pneumonia.
In one embodiment, the viral pneumonia is a critically ill covd-19 pneumonia.
In one embodiment, the viral pneumonia is moderate covd-19 pneumonia.
In one embodiment, the viral pneumonia is moderate-severe covd-19 pneumonia.
In one embodiment, the method further comprises administering a single (second) intravenous dose of tolizumab based on body weight to the patient 8-12 hours (or 8-24 hours) after the first dose, wherein the second dose based on body weight is 8mg/kg (e.g., wherein less than or equal to 800mg of tolizumab is administered to the patient at the second dose).
In one embodiment, the method further comprises administering a single (second) intravenous dose of tolizumab based on body weight to the patient 8-11 hours after the first dose, wherein the second dose based on body weight is 8mg/kg (e.g., wherein less than or equal to 800mg of tolizumab is administered to the patient at the second dose).
In one embodiment, only a single weight-based dose, 8mg/kg (.ltoreq.800 mg), is administered to the patient.
In one embodiment, only two weight-based doses of 8mg/kg each (800 mg each) are administered to the patient.
In one embodiment, the second dose is administered after the patient has not experienced an improvement or worsening of the clinical state after the first dose.
In one embodiment, the second dose is administered after the patient has not improved or greater than or equal to one category of exacerbations in the ordered list of clinical states after the first dose.
In one embodiment, the second dose is administered after the patient experiences ≡one category of exacerbations on an ordered scale of clinical status after the first dose.
In one embodiment, the order table is a 7-category order table.
The present invention provides methods of treating pneumonia (e.g., viral pneumonia, coronavirus pneumonia, or covd-19 pneumonia) with anti-IL 6 antagonists (e.g., anti-IL 6 receptor antibodies, such as tolizumab, sarilumab, sha Lizhu mab, and/or TZLS-501), resulting in a greater improvement in clinical outcome than standard of care (SOC).
Methods for confirming improvement in clinical outcome compared to SOC include, but are not limited to, any one or more of:
1. clinical results measured on an ordered list of clinical states (e.g., on day 28 and/or day 60);
2. clinical results measured on the 7-category ordering scale of clinical status (e.g., on day 28 and/or day 60);
3. clinical results including time to improve at least 2 categories relative to baseline arrival on a 7-category order scale for clinical status (e.g., on day 28 and/or day 60);
4. clinical results including Time To Clinical Improvement (TTCI), defined as maintaining national warning score 2 (NEWS 2) of 2 for less than or equal to 24 hours;
5. incidence of mechanical ventilation (e.g., on day 28 and/or day 60);
6. ventilator-free days (e.g., to day 28);
7. days without organ failure (e.g., to day 28 and/or day 60);
8. intensive Care Unit (ICU) occupancy (e.g., by day 28 and/or day 60);
icu residence time (e.g., to day 28 and/or day 60);
10. time to clinical failure, e.g., defined as time to death, mechanical ventilation, ICU check-in or withdrawal, subject to first occurrence;
11. mortality (e.g., days 7, 14, 21, 28, and 60 after treatment on day 1).
12. Time to discharge;
13. time to ready for discharge (e.g. as evidenced by stable oxygen saturation with normal temperature and breathing rate, ambient air or supplemental oxygen of 2L or less)
14. Duration of oxygen supplementation;
15. incidence of vasopressor use;
16. duration of vasopressor use;
17. incidence of extra-corporeal pulmonary oxygenation (ECMO);
duration of ecmo;
in one embodiment, the method of treatment using an IL6 antagonist is associated with an acceptable safety outcome as compared to standard of care (SOC). Exemplary security results include any one or more of the following:
1. incidence and severity of adverse events;
2. severity of adverse events determined according to the national cancer institute general term for adverse events standard (NCI CTCAE) v5.0
3. Covd-19 (SARS-CoV-2) viral load over time;
4. time to reverse transcriptase polymerase chain reaction (RT-PCR) virus negative;
5. infection after treatment; and
6. variation of target clinical laboratory test results from baseline.
Herein, SOC of pneumonia, particularly viral pneumonia (e.g., covd-19 pneumonia), includes any one or more (e.g., one, two, or three) of:
1. Supportive care;
2. one or more antiviral agents;
3. one or more corticosteroids, such as low-dose corticosteroids.
In one embodiment, the SOC includes supportive care. Examples of supportive care include, but are not limited to:
1. oxygen therapy (e.g., via a mask or nasal catheter, high flow nasal oxygen therapy or non-invasive mechanical ventilation, pulmonary expansion via extracorporeal membrane oxygenation (ECMO), etc.);
2. circulatory support (e.g., fluid resuscitation, microcirculation augmentation, and/or vasoactive drugs);
3. renal replacement therapy;
4. plasma therapy;
5. blood purification therapy;
6. xuebijing injection (e.g., 100 mL/day, twice a day); and
7. microecologics (e.g., probiotics, prebiotics, and synbiotics), and the like.
In one embodiment, SOC includes treatment with one or more antiviral agents (preferably only one or two) antiviral agents. Exemplary antiviral therapies include, but are not limited to:
1. interferon-alpha (e.g., via nebulization; e.g., about 500 ten thousand units or equal amounts per adult, 2mL of sterile injectable water added; e.g., twice daily via aerosol inhalation);
2. lopinavir/ritonavir (e.g., 200mg/50mg per capsule, 2 capsules each, twice daily for adults, e.g.,. Ltoreq.10 days);
3. Ribavirin (e.g., in combination with interferon-alpha or lopinavir/ritonavir, e.g., 500mg each time for adults, 2-3 times daily intravenously, e.g.,. Ltoreq.10 days);
4. chloroquine or hydroxychloroquine phosphate (e.g. for an adult of 18-65 years old; e.g. 500mg each time for 7 days if the body weight is greater than 50 kg; 500mg each time for 1 st and 2 nd days if the body weight is less than 50 kg; 500mg each time for 3 rd to 7 th days), optionally together with azithromycin; and
5. wu Mifei norvir (e.g. 200mg for an adult, e.g. 3 times daily, e.g. 10 days).
In one embodiment, the SOC includes treatment with a corticosteroid, e.g.
1. Wherein the patient has progressive deterioration of oxygenation, rapid X-ray progression and/or excessive inflammatory response;
2. prednisone, prednisolone, methylprednisolone sodium succinate, dexamethasone triamcinolone, hydrocortisone, and/or betamethasone;
3. prednisone, methylprednisolone, hydrocortisone or dexamethasone.
4. Methylprednisolone;
"low dose" corticosteroid;
6. the applied corticosteroid is less than or equal to 1-2 mg/kg/day;
7. Methyl prednisolone is less than or equal to 1-2 mg/kg/day;
8. the methylprednisolone is less than or equal to 1-2 mg/kg/day for 3-5 days.
The invention also relates to a method of treating pneumonia (including viral pneumonia, e.g., coronavirus pneumonia, such as covd-19 pneumonia) in a patient comprising:
a. administering a first weight-based 8mg/kg intravenous dose of tolizumab to a patient; and
b. further comprising administering a second weight-based intravenous dose of 8mg/kg of tolizumab to the patient 8-12 hours after the first dose (e.g., 8-11 hours after the first dose) or 8-24 hours, wherein after the first dose the patient does not experience improvement or ≡a category of exacerbation on an ordered scale of clinical status.
In another embodiment, the invention provides a method of treating pneumonia (including viral pneumonia, e.g., coronavirus pneumonia, such as covd-19 pneumonia) in a patient comprising administering to the patient an effective amount of an IL6 antagonist to achieve a greater improvement in clinical outcome than standard of care (SOC), as measured by the ordinal scale of clinical status.
In one embodiment, the IL6 antagonist binds to an IL6 receptor.
In one embodiment, the IL6 antagonist is tolizumab, sarilumab, sha Lizhu mab and/or TZLS-501.
In another embodiment of any of the methods herein, the patient can be treated with SOC in conjunction with an IL6 antagonist. SOC includes, for example, supportive care, antiviral agents, and/or low dose corticosteroids as disclosed above.
In another embodiment, the invention provides a method of treating Acute Respiratory Distress Syndrome (ARDS) in a patient without elevated IL6 levels comprising administering an IL6 antagonist (e.g., an IL6 receptor antibody, such as tolizumab) to the patient. Patients with ARDS may be suffering from viral pneumonia, such as covd-19 pneumonia.
These additional drugs described herein are typically used in the same dosages and routes of administration as used above, or about 1% to 99% of the dosages previously used. If these additional drugs are used entirely, they are preferably used in an amount lower than in the absence of the first drug (particularly in subsequent administrations after the initial administration of the first drug) to eliminate or reduce the side effects caused thereby.
The combined administration of additional agents includes co-administration (co-administration) using separate formulations or single agent formulations, as well as sequential administration in any order, wherein it is preferred that both (or all) of the active agents (agents) exert their biological activity simultaneously over a period of time.
V. products
In another embodiment of the invention, an article of manufacture is provided comprising a material useful in the treatment of the aforementioned pneumonia (including viral pneumonia, e.g., coronavirus pneumonia such as covd-19 pneumonia) and/or Acute Respiratory Distress Syndrome (ARDS).
The article of manufacture optionally further comprises a package insert with instructions for treating pneumonia (including viral pneumonia, e.g., coronavirus pneumonia, such as covd-19 pneumonia) and/or Acute Respiratory Distress Syndrome (ARDS) in a subject, wherein the instructions indicate that treatment with an antibody as disclosed herein can treat pneumonia (e.g., including viral pneumonia, e.g., coronavirus pneumonia, such as covd-19 pneumonia) and/or Acute Respiratory Distress Syndrome (ARDS).
Further details of the invention are illustrated by the following non-limiting examples. The disclosures of all references in this specification are expressly incorporated herein by reference.
Example 1: randomization, double-blind, placebo-controlled, multicenter studies to evaluate the presence of tobramycin in patients with severe cases Safety and efficacy in patients with covd-19 pneumonia
This is a phase III, randomized, double-blind, placebo-controlled, multicenter study aimed at assessing efficacy and safety of TCZ-combined SOC in hospitalized adult patients with severe COVID-19 pneumonia as compared to matched placebo-combined SOC. About 330 patients diagnosed with covd-19 pneumonia and meeting central admission criteria will receive treatment. The following outlines the specific targets and corresponding endpoints of the study.
Efficacy targets
Main efficacy goal
The primary efficacy objective of this study was to evaluate the efficacy of TCZ in combination with SOC in treating severe covd-19 pneumonia compared to placebo according to the following endpoints:
1. assessment of clinical status using 7-class order scale on day 28
Secondary efficacy objective
The secondary efficacy objective of this study was to evaluate the efficacy of TCZ in combination with SOC in treating severe covd-19 pneumonia compared to placebo according to the following endpoints:
1. time To Clinical Improvement (TTCI), defined as a national warning score 2 (new 2) of 2 maintained for less than or equal to 24 hours
2. Time to improve at least 2 categories relative to baseline arrival on a 7-category sequence scale for clinical status
3. Incidence of mechanical ventilation
4. Ventilator-free days to day 28
5. Days without organ failure to day 28
6. Intensive Care Unit (ICU) occupancy rate
Icu check-in duration
8. Time to clinical failure, defined as time to death, mechanical ventilation, ICU check-in or withdrawal (based on the first occurrence)
9. Mortality on days 7, 14, 21, 28 and 60
10. Time to discharge or "ready to discharge" (as evidenced by proper body temperature and respiratory rate, stable oxygen saturation with ambient air or supplemental oxygen of 2L or less)
11. Duration of oxygen supplementation
Other efficacy goals
A further efficacy objective of this study was to evaluate the efficacy of TCZ in combination with SOC in treating severe covd-19 pneumonia compared to placebo according to the following endpoints:
1. incidence of vasopressor use
2. Duration of vasopressor use
3. Incidence of extracorporeal membrane oxygenation (ECMO)
Duration of ECMO
Security target
The safety objective of this study was to evaluate the safety of TCZ versus placebo in combination with SOC for the treatment of severe covd-19 pneumonia according to the following endpoints:
1. incidence and severity of adverse events, wherein severity is determined according to the national cancer institute adverse event common terminology standard (NCI CTCAE) v5.0
2. Covd-19 (SARS-CoV-2) viral load over time, as collected by nasopharyngeal swab and bronchoalveolar lavage (BAL) samples, if applicable;
3. time to reverse transcriptase polymerase chain reaction (RT-PCR) virus negative
4. Proportion of patients with any post-treatment infection
5. Variation of target clinical laboratory test results from baseline
Pharmacodynamic targets
The pharmacodynamic objective of this study was to characterize the pharmacodynamic effects of TCZ in patients with covd-19 pneumonia via longitudinal measurement of the following analytes relative to baseline:
Serum concentrations of IL-6, sIL-6R, ferritin and CRP at the indicated time points
Pharmacokinetic targets
The PK objective of this study was to characterize TCZ PK profile in patients with covd-19 pneumonia based on the following endpoints:
serum concentration of TCZ at the indicated time points
Description of the study
The patient must be over 18 years old and confirm PCR positivity of infection with covd-19, including any samples (e.g., respiratory tract, blood, urine, feces, other body fluids) according to WHO criteria. When the patients are in group, the patients must have SpO 2 93% or less or PaO 2 /FiO 2 < 300mmHg, even while SOC is being accepted, SOC may include antiviral treatment, low dose steroids, and supportive care.
The treating physician considers that patients who will or will not be able to avoid progressing to death within the next 24 hours, whether or not treatment is provided, will be excluded from the study. Patients with active Tuberculosis (TB) or suspected active bacteria, fungi, viruses or other infections (except covd-19) will be excluded from the study.
Patients will be randomized at a 2:1 ratio as soon as possible after screening and receive either TCZ or placebo-matched blind treatment, respectively. Study treatment must be given in combination with SOC. Randomization will be layered by geographic area (north america, europe, etc.) and mechanical ventilation (yes, no).
Patients assigned to the TCZ group will receive one 8mg/kg TCZ infusion with a maximum dose of 800mg, while patients assigned to the placebo group will receive one placebo infusion in addition to SOC.
For both groups, if there is a worsening or no improvement in clinical signs or symptoms (e.g., a worsening of at least one category in the 7-category sequential scale of sustained fever or clinical status), then TCZ or placebo blind therapy may be infused once (8 m/kg, maximum dose of 800 mg) 8-12 hours (or 8-24 hours) after the initial infusion.
After day 28
Following the first dose of study drug, the patient will be followed up for a total of 60 days.
For discharged patients, access was made between day 28 and study completion by telephone.
Standard supportive care will be given in accordance with clinical practice during the study.
From the start of randomization, patients will be followed up for 60 days.
Control group
The study will compare the efficacy and safety of TCZ IV with matched placebo-combined SOC. Despite the lack of targeted therapy for covd-19, patients suffering from severe covd-19 pneumonia often include supportive care in SOC and may include available antiviral drugs and low-dose corticosteroids prescribed by local treatment guidelines.
Patient(s)
The study was aimed at recruiting about 330 hospitalized patients with severe covd-19 pneumonia.
Inclusion criteria
The patient must meet the following conditions to enter the study:
1. age is greater than or equal to 18 years old
2. Hospitalization (including PCR positivity of any sample; e.g., respiratory tract, blood, urine, stool, other body fluids) for COVID-19 pneumonia was confirmed according to WHO standard and confirmed by chest X-ray or CT scan
3.SpO 2 Less than or equal to 93 percent or PaO2/FiO 2 <300mmHg
Exclusion criteria
Patients meeting any of the following criteria will be excluded from the study entry:
1. severe allergic reactions to TCZ or other monoclonal antibodies are known
2. Active TB infection
3. Suspected active bacterial, fungal, viral or other infections (except for covd-19)
4. Researchers believe that progression to death is imminent or unavoidable within the next 24 hours, whether or not treatment is provided.
5. Oral anti-rejection or immunomodulatory drugs (including TCZ) have been accepted for the last 6 months
6. Participation in other drug clinical trials (approval by Medical Monitor permits participation in the COVID-19 antiviral trial)
7. ALT or AST >10 XULN (according to local laboratory reference range) was detected within 24 hours at screening or baseline
8. ANC < 1000/. Mu.L at screening or baseline (according to local laboratory reference range)
9. Platelet count at screening or baseline < 50000/. Mu.L (according to local laboratory reference range)
10. Pregnancy or lactation, or pregnancy test positive before administration
11. Treatment with study drug (if approved by the media Monitor, permissible study covd-19 antiviral drug) over a randomized 5 half-life or 30 days (whichever is longer)
12. At the discretion of the researcher, any serious medical condition or abnormality that prevents the patient from safely participating in and completing the clinical laboratory test of the study
7-class order table
Assessment of clinical status using the 7-class order scale will be recorded at baseline on day 1 and then again once daily in the morning (8 am to 12 pm) during hospitalization. The ordered list categories are as follows:
1. discharge (or "ready to discharge", as evidenced by normal body temperature and respiratory rate, ambient air or oxygen saturation stabilization with 2L oxygen supplementation)
2. non-ICU hospital ward (or "ready to hospital ward") and does not require supplemental oxygen
3. non-ICU hospital ward (or "ready to hospital ward") and need to be supplemented with oxygen
ICU or non-ICU hospital ward, requiring non-invasive ventilation or high flow of oxygen
Icu, requiring intubation and mechanical ventilation
Icu, requiring ECMO or mechanical ventilation and additional organ support (e.g. vasopressors, renal replacement therapy)
7. Death of
In general, patients with blood oxygen saturation of 90% or less should be considered to be promoted to a higher clinical status category, while patients with blood oxygen saturation of 96% or more should be considered to be promoted to a lower clinical status category. Patients who are supplemented with oxygen should be assessed at least once daily and consider reducing or stopping oxygen support. The actual change in support level will be determined by the clinician treating the patient, at his discretion of the overall condition of the patient, and possibly by other clinical and non-clinical considerations.
Normothermic is defined as an oral, rectal or tympanic temperature of 36.1-38.0 ℃. The normal breathing rate is defined as 12-20 breaths per minute.
National Early Warning Score (NEWS) 2
NEWS2 scores are published at the Royal physician's college (Royal College of Physicians). National Early Warning Score (NEWS) 2. Assessment of acute disease severity in NHS was normalized. London: RCP (2017).
It involves evaluating the following parameters.
SpO 2 =blood oxygen saturation; CVPU = confusion, sound, pain, unconsciousness.
Should be based on the SpO present in the above table 2 Blood oxygen saturation was scored on either scale 1 or 2. SpO (SpO) 2 Table 2 is for patients with target blood oxygen saturation requirements of 88% -92% (e.g., in patients with advanced lung disease such as chronic obstructive pulmonary disease [ COPD ]]In patients with associated hypercapnic respiratory failure). This applies only to patients who were previously or currently admitted to the hospital and were confirmed to have hypercapnic respiratory failure by blood gas analysis.
Using SpO 2 The decision of table 2 should be made by the attending physician and should be recorded in the eCRF. At all other placesIn the case of SpO should be used 2 Scale 1.
For the physiological parameter "air or oxygen? ": any patient that needs to use oxygen or other forms of ventilation to maintain oxygen saturation and support breathing should be assigned a score of 2.
The level of consciousness should be recorded at the time of evaluation according to the optimal clinical condition of the patient. Patients assessed as "alert" (a) should be assigned a score of 0. Patients assessed as "new confusion" (C), "sound-responsive" (V), "pain-responsive" (P) or "unconscious" should be assigned 3 points.
Respiratory rate, systolic blood pressure, pulse and body temperature should be scored according to the above table.
The NEWS2 values will be calculated electronically by the sponsor over the duration of the study based on vital sign parameters entered by the researcher in the appropriate eCFs.
Example case calculation:
a82 year old woman was admitted, tested positive for COVID-19, and sent to the highly dependent ward for noninvasive ventilation. Her observations and corresponding NEWS2 scores were as follows:
physiological parameters Observations of Component scoring
Respiratory rate (per minute) 26 3
Oxygen saturation (SpO) 2 ％) 95％ 1
Oxygen supplementation Is that 2
Systolic blood pressure (mmHg) 95 2
Pulse rate (bpm) 109 1
Consciousness level New confusion 3
Body temperature (DEG C) 39 1
Total NEWS2 score 13
Liver function
The liver function of the patient should be assessed on day 1 prior to each dose of TCZ or matched placebo. In clinical trials, mild and moderate elevations in hepatic transaminase were observed with TCZ treatment. The recommended TCZ dose adjustments for elevated liver enzymes in these populations are not applicable to the present study due to single dose treatment (and possibly additional infusion) of TCZ or placebo. ALT or AST elevation (> 3 XULN) combined with total bilirubin elevation (> 2 XULN) or clinical jaundice in the absence of cholestasis or other hyperbilirubinemia causes is considered an indicator of severe liver injury (defined by Hai's law). Adverse events may be reported when any of the following occurs:
1. ALT or AST > 3 XULN combined with total bilirubin > 2 XULN occurring during treatment
2. ALT or AST > 3 XULN baseline values present in treatment in combination with clinical jaundice Results and conclusions
It is contemplated that treatment herein with an intravenous dose of tobulab based on body weight (8 mg/kg +.800 mg), optionally (if the patient's clinical signs or symptoms are not improved or worsened, as reflected by at least one type of worsening on the clinical status order scale), at 8-12 hours (including 8-11 hours) or 8-24 hours after the initial dose, a single second weight-based (8 mg/kg +.800 mg) dose of tobulab will reach any one or more of the primary, secondary, or additional endpoints while having acceptable toxicity according to the safety endpoints specified herein.
Example 2: tozumaab and adefovir combination therapy for covd-19 pneumonia
This is a randomized, double-blind, double-simulation study with 3 groups of randomized 4:1:1 assignments to approximately 450 patients:
group A: TCZ plus RDV+SOC
Group B: TCZ+SOC
Group C: RDV+SOC
The TCZ group will be administered 8mg/kg (maximum dose of 800 mg) and if the patient's clinical signs or symptoms worsen or do not improve (e.g., as reflected by persistent fever or at least one category worsening on the 7-category ordering scale of the clinical status), one more blind treatment of TCZ (8 mg/kg, maximum dose of 800 mg) may be infused 8-24 hours after the initial infusion.
200mg of RDV was administered on day 1 followed by 100mg of RDV on days 2, 3, 4 and 5, or 200mg of RDV on day 1 followed by 100mg of RDV on days 2, 3, 4, 5, 6, 7, 8, 9 and 10.
The SOC of patients with severe covd-19 pneumonia typically includes supportive care and may include antiviral drugs other than RDV (preferably only one other antiviral therapy) and low-dose corticosteroids prescribed by local therapy guidelines.
The "inclusion criteria" and "exclusion criteria" are as described above in example 1.
Efficacy and safety targets are as described in example 1.
It is expected that combination therapy of TCZ and RDV will reach any one or more of the primary, secondary or additional endpoints while having acceptable toxicity. It is further expected that combination therapy of tcz+rdv+soc will be more effective in treating covd-19 pneumonia than tcz+soc (i.e., without RDV) and rdv+soc (i.e., without TCZ).
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Claims (11)

1. A method of treating viral pneumonia in a patient comprising administering to said patient an effective amount of a combination of tolizumab and adefovir.
2. The method of claim 1, wherein the viral pneumonia is covd-19 pneumonia.
3. The method of claim 2, wherein the viral pneumonia is severe pneumonia.
4. The method of claim 3, wherein the viral pneumonia is severe covd-19 pneumonia.
5. The method of any one of the preceding claims, further comprising treating the patient with a covd-19 standard of care (SOC).
6. The method of claim 5, wherein the SOC comprises one or more of: supportive care, antiviral agents other than adefovir, and low dose corticosteroids.
7. The method of any one of the preceding claims, wherein the effective amount of tolizumab comprises a first 8mg/kg intravenous dose of tolizumab on a weight basis, optionally followed by a second 8mg/kg intravenous dose of tolizumab on a weight basis 8-24 hours after the first dose.
8. The method of any one of the preceding claims, wherein the effective amount of adefovir comprises an initial single dose of 200mg followed by 100mg per day.
9. The method of claim 8 comprising 5 to 10 total doses of adefovir.
10. The method of any one of the preceding claims, wherein an effective amount of the combination is more effective in treating the viral pneumonia as compared to rituximab without adefovir and as compared to adelomab Wei Motuo.
11. The method of claim 7, wherein a second body weight-based intravenous dose of tolizumab is administered to the patient 8-24 hours after the first dose.
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US202063011889P 2020-04-17 2020-04-17
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PCT/US2021/023061 WO2021194860A1 (en) 2020-03-23 2021-03-19 Tocilizumab and remdesivir combination therapy for covid-19 pneumonia

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