WO2022262879A1 - Uso de anticuerpos monoclonales contra el receptor del factor de crecimiento epidérmico en el tratamiento de pacientes con insuficiencia respiratoria aguda hipoxémica - Google Patents
Uso de anticuerpos monoclonales contra el receptor del factor de crecimiento epidérmico en el tratamiento de pacientes con insuficiencia respiratoria aguda hipoxémica Download PDFInfo
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- 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
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to the branches of Biotechnology and Medicine and especially to the use of monoclonal antibodies (MAb) directed against the epidermal growth factor receptor in the treatment of acute hypoxemic respiratory failure.
- MAb monoclonal antibodies
- hypoxemic acute respiratory failure is the leading cause of emergency admissions. The mortality rate is almost 20%.
- the most common etiologies are pneumonia, neurological causes, non-pulmonary sepsis, and chronic obstructive pulmonary disease.
- the disease is characterized by dyspnea at rest, a blood pressure of O2 (PO2) less than 60 mmHg and/or a blood pressure of CO2 (PCO2) greater than 45 mmHg (Joao D et al. (2019) J Crit Care 49: 84-91., Piriano T et al. (2019) Respir Care. 64(6):638-646).
- ARDS acute respiratory distress syndrome
- ARDS acute respiratory distress syndrome
- It is the result of a systemic inflammatory disease that results in pulmonary infiltrate, edema, and hypoxia. This process is characterized at the cellular level by loss of integrity of the alveolar-capillary membrane, excessive infiltration of neutrophils, and release of pro-inflammatory cytokines and chemokines (Shan X et al. (2017) Oncotarget;8(16):26648 -61).
- Epidermal growth factor receptor is a 170 kDa membrane glycoprotein, which controls fundamental cellular processes, including cell migration, the cell cycle, cell metabolism and survival, as well as cell proliferation and differentiation.
- EGFR Epidermal growth factor receptor
- the physiological function of EGFR is to regulate epithelial tissue development and homeostasis (Mendelsohn J, Baselga J. (2006) Semin Oncol.;33(4):369-85).
- EGFR and its ligands are upregulated in multiple tumors of epithelial origin, including non-small cell lung cancer, gliomas, head and neck, cervical, and esophageal tumors (Mendelsohn J, Baselga J. (2006) Semin Oncol .;33(4):369-85). EGFR overexpression in tumors is correlated with increased metastasis, decreased survival, and a poor prognosis.
- TKIs tyrosine kinase inhibitors
- gefitinib including gefitinib, erlotinib and osimertinib
- anti-EGFR MAbs such as cetuximab, panitumumab and nimotuzumab
- Acute respiratory failure affects a positive regulation and over expression of EGFR.
- EGFR activation results in more severe lung pathology.
- the major node in pulmonary fibrosis is the EGFR pathway, which controls many cascades of cell proliferation, mucus secretion, inflammatory response, and tissue repair (Venkataraman T, Frieman MB. (2017) Antiviral Res.;143:142-50 ).
- TKIs can induce hypoxemic acute respiratory failure, secondary to interstitial pneumonitis. This adverse event occurs with a low frequency of 1.1 to 2.2%, but can be fatal, accounting for 58% of all EGFR-TKI treatment-related deaths (Ohmori T et al. (2021) Int J Mol Sci.;22(2):792). Patients in Japan show a significantly higher incidence of pneumonitis, with no known cause at this time (Suh CH et al. (2016) Lung Cancer;123:60-9).
- the inventors of the present invention when administering the mAb nimotuzumab to patients suffering from hypoxemic acute respiratory failure or ARDS, observed improvements in ventilatory parameters, inflammation, lung lesions and their survival.
- the present invention relates to the use of MAbs directed against the EGFR in the treatment of diseases that lead to acute hypoxemic respiratory failure of infectious origin and in particular in that which is classified as ARDS.
- acute respiratory failure is of infectious origin and can be caused by microorganisms that are selected from the group comprising: coronavirus, rhinovirus, cytomegalovirus, Epstein Barr, influenza virus, respiratory syncytial virus, Streptococcus pyogenes , Streptococcus pneumoniae, Haemophilus influenzae , Escherichia coli, Pseudomona aeruginosa, Proteus mirabilis, Enterobacter spp, Klebsiella spp, Acinetobacter spp, Staphilococcus spp, Serratia spp Cryptococcus neoformans, Rhizopus spp, Aspergillus spp, Pneumocyrzomus spp and Rpphicormus spp.
- microorganisms that are selected from the group comprising: coronavirus, rhinovirus, cytomegalovirus, Epstein Barr, influenza virus, respiratory syncytial virus,
- anti-EGFR mAbs contemplated by the present invention that can be used in the treatment of hypoxemic acute respiratory failure or ARDS are nimotuzumab, cetuximab, and panitumumab.
- the present invention relates to a treatment method for a subject in need that comprises the administration of an anti-EGFR mAb by intravenously or subcutaneously in a dose range of 1 mg/Kg of weight to 6 mg/Kg of weight for at least two times and up to a maximum of five times spaced between 72 and 168 hours.
- the mAbs against EGFR that are used in the present invention are administered as part of pharmaceutical compositions containing the mAbs as active ingredient and pharmacologically appropriate excipients for parenteral use.
- these MAbs are nimotuzumab whose sequence is described in US patent 5,891,996, cetuximab described in US patent 6,217,866 B1 and panitumumab whose sequence is described in US 5,558,864 B1.
- the present invention describes the use of anti-EGFR antibodies, in the treatment of acute hypoxemic acute respiratory failure or ARDS.
- the use is described for the case of patients where the acute respiratory failure or respiratory distress syndrome is caused by an infectious agent, for example, a virus, a bacterium or a fungus.
- anti-EGFRs can be used to treat acute respiratory failure or ARDS induced by viruses such as coronaviruses, rhinoviruses, cytomegalovirus, Epstein Barr virus, influenza virus, and respiratory syncytial virus.
- bacterial infections in particular those caused by streptococci, pneumococci or staphylococci, Haemophilus influenzae, Escherichia coli, Pseudomona aeruginosa, Proteus mirabilis, Enterobacter spp, Klebsiella spp, Acinetobacter spp and Serratia spp are protected.
- infectious agent is a fungus, this can be Cryptococcus neoformans, Rhizopus spp, Aspergillus spp, Pneumocystis spp, Mucor spp or Rhizomucor spp.
- anti-EGFR antibodies as described in the present invention ameliorate the symptoms and signs of hypoxemic acute respiratory failure or acute respiratory distress syndrome.
- a particular advantage of the proposed treatment is that it does not induce immunodeficiency in the patient, unlike other conventional therapies based on steroids or other immunosuppressants.
- the preservation of immunocompetence in the treated patient reduces the possibility of the emergence of other opportunistic infections, very common in severe or critical patients.
- Patients receiving anti-EGFR antibody therapy are preferably admitted to an intensive or intermediate care unit, although they may also be in a conventional unit.
- the anti-EGFR MAbs will be applied to patients intravenously or subcutaneously, in a dose range between 1 mg/Kg of weight and 6 mg/Kg of weight, which corresponds approximately between 50 and 600 mg total respectively.
- doses between 1.42 mg/kg and 2.85 mg/kg will be used.
- These MAbs will be administered to the patient at least twice and with a maximum of 5 doses.
- the time between two consecutive administrations will be between 72 and 168 hours.
- the preferred scheme is two to three doses spaced every 72 hours, using a loading dose of 200 mg and subsequent doses of 100 mg.
- the dose and regimen to be used for the different anti-EGFR mAbs may be adjusted by evaluating their ability to recognize EGFR.
- the serial or concomitant combination of anti-EGFR antibodies with antiviral or antibiotic therapies is also an object of the present invention.
- antibiotics to be combined are, among others, those of the cephalosporin family such as ceftriaxone, macrolides such as azithromycin, glycopeptides such as vancomycin, beta-lactams such as meropenem and oxazolidinones such as linezolid.
- antivirals to be combined will be, among others, type 1 and type 2 interferons, antiretrovirals used in the treatment of HIV such as remdesivir.
- the antibiotic or antiviral regimens to be used will be those conventionally used for each drug, while the anti-EGFR antibody regimen will respond to what is described above.
- the object of the present invention is the serial or concomitant combination of anti-EGFR antibodies, with other anti-inflammatory therapies or anticoagulant therapies such as steroids or other immunomodulatory drugs and with anticoagulant therapies such as low molecular weight fractionated heparin or sodium heparin, unfractionated.
- FIG. 1 Chest computed tomography of three patients treated with nimotuzumab. Sequential images A) on admission, B) on hospital discharge and C) follow-up between 30-60 days after discharge.
- Figure 4 Radiological evolution of three patients before and after treatment with nimotuzumab: A) JMTR patient, B) JHV patient, C) MESS patient.
- Figure 5 Global evolution of patients with COVID-19 treated with nimotuzumab.
- Figure 6. D-dimer values in patients treated with nimotuzumab.
- Example 1 The use of nimotuzumab reduces the mortality rate from SARS-CoV-2 in patients with hypoxemic acute respiratory failure.
- Table 1 shows that the use of nimotuzumab reduced the mortality rate by 16% in relation to the control group.
- the survival rate for severe COVID-19 patients ranges from 77-81% following the use of best supportive therapy including anticoagulation and steroids and an anti-IL6 receptor antibody in some patients (tocilizumab ) (Group RC (2021 ) Lancet;397(10285): 1637-45; Rosas IO et al. (2021 ) N Engl J Med.;384(16):1503-16).
- the recovery data of nimotuzumab (92.85%) in combination with the therapy established in the Cuban protocol compare very favorably with Cuban control patients (77%) and from multinational trials (77-81%).
- Figures 1A and B show extensive areas of ground glass opacities, consolidation of the airspace in the exudative phase, and decreased lung volumes in the organizing and fibrotic phase.
- Figure 1C on the other hand, the 3 patients showed resolution of the pulmonary inflammatory lesions and no signs of fibrosis.
- Example 2 The use of nimotuzumab improves the ventilatory parameters of treated patients.
- Example 3 Treatment with nimotuzumab improves the inflammatory parameters of the treated patients.
- LDFI and IL-6 were measured before and after treatment with nimotuzumab, the latter using ELISA (Quantikine). All the patients had steroid treatment before the administration of the monoclonal antibody.
- Figure 3 shows that a decrease in LDFI occurs after 2 doses of mAb nimotuzumab.
- Table 2 shows IL-6 concentrations before and at different times of nimotuzumab treatment.
- Example 4 Treatment with nimotuzumab improves the area affected by multifocal interstitial pneumonia. In 8 patients with different times of evolution of COVID-19 after 2 doses of nimotuzumab, the percentage of affected area of both lung fields (right lung and left lung) was calculated. Table 3 shows these results.
- Example 4 Patients with ARDS caused by COVID-19 have clinical improvement after treatment with nimotuzumab.
- Example 5 Treatment with nimotuzumab produces a decrease in D-dimer in severe COVID-19 patients.
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Abstract
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
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US18/569,714 US20240279348A1 (en) | 2021-06-14 | 2022-06-06 | Use of monoclonal antibodies against the epidermal growth factor receptor in the treatment of patients with hypoxemic acute respiratory failure |
MX2023014863A MX2023014863A (es) | 2021-06-14 | 2022-06-06 | Uso de anticuerpos monoclonales contra el receptor del factor de crecimiento epidermico en el tratamiento de pacientes con insuficiencia respiratoria aguda hipoxemica. |
KR1020247000130A KR20240021205A (ko) | 2021-06-14 | 2022-06-06 | 상피 성장 인자 수용체에 대한 단클론항체의 저산소성 급성 호흡부전 환자의 치료에 있어서의 용도 |
CA3222462A CA3222462A1 (en) | 2021-06-14 | 2022-06-06 | Use of monoclonal antibodies against the epidermal growth factor receptor in the treatment of patients with acute hypoxaemic respiratory failure |
AU2022294928A AU2022294928A1 (en) | 2021-06-14 | 2022-06-06 | Use of monoclonal antibodies against the epidermal growth factor receptor in the treatment of patients with acute hypoxaemic respiratory failure |
JP2023577206A JP2024521969A (ja) | 2021-06-14 | 2022-06-06 | 低酸素血症性急性呼吸不全患者の治療における上皮成長因子受容体に対するモノクローナル抗体の使用 |
EP22735764.7A EP4356926A1 (en) | 2021-06-14 | 2022-06-06 | Use of monoclonal antibodies against the epidermal growth factor receptor in the treatment of patients with acute hypoxaemic respiratory failure |
CN202280042158.8A CN117500523A (zh) | 2021-06-14 | 2022-06-06 | 针对表皮生长因子受体的单克隆抗体治疗患有低氧血症型急性呼吸衰竭的患者的用途 |
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CN (1) | CN117500523A (es) |
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2022
- 2022-06-06 US US18/569,714 patent/US20240279348A1/en active Pending
- 2022-06-06 AU AU2022294928A patent/AU2022294928A1/en active Pending
- 2022-06-06 WO PCT/CU2022/050006 patent/WO2022262879A1/es active Application Filing
- 2022-06-06 KR KR1020247000130A patent/KR20240021205A/ko unknown
- 2022-06-06 CN CN202280042158.8A patent/CN117500523A/zh active Pending
- 2022-06-06 EP EP22735764.7A patent/EP4356926A1/en active Pending
- 2022-06-06 MX MX2023014863A patent/MX2023014863A/es unknown
- 2022-06-06 CA CA3222462A patent/CA3222462A1/en active Pending
- 2022-06-06 JP JP2023577206A patent/JP2024521969A/ja active Pending
- 2022-06-09 TW TW111121437A patent/TW202317621A/zh unknown
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KR20240021205A (ko) | 2024-02-16 |
MX2023014863A (es) | 2024-01-16 |
CA3222462A1 (en) | 2022-12-22 |
JP2024521969A (ja) | 2024-06-04 |
US20240279348A1 (en) | 2024-08-22 |
TW202317621A (zh) | 2023-05-01 |
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EP4356926A1 (en) | 2024-04-24 |
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